Pharma IP Cases Part A

Pharma IP Cases

Sanjay Boldhane

M. Pharm., Ph. D.

1

Turmeric

USPTO Vs CSIR

Ground: Traditional Knowledge

2

Patents Granted on TM

The grant of patents linked to indigenous knowledge of the developing world needs to be addressed jointly by the developing and developed world.

A recent study by an Indian expert group examined randomly selected 762 US patents which were granted under

A61K35/78 Out of these patents, 374 patents were found to be based on traditional

knowledge The governments in the Third World, as well as members of the

public, are rightly concerned about the grant of patents for non-original inventions in the traditional knowledge systems of the developing world.

3

CSIR and Turmeric Case

US Pat No. 5,401,504 Title : Use of turmeric in wound healing.

Date of Application28/12/1993, Patent Granted : 28/03/1995

Inventors: Suman K. Das and Hari Har P. Cohly,

Assignee: University of Mississippi Medical Centre, Jackson

Request for re-examination of the patent was filled by CSIR on 28 October 1996.

The first re-examination result rejected all the six claims based on the references submitted by CSIR on the ground of 'anticipated references'

CSIR challenged the patent on the ground that it lacked novelty 32 references (some of them being more than one hundred years old, in Sanskrit, Urdu and Hindi),

which showed that this finding was well known in India prior to filing of this patent. Paper published in 1953 in the Journal of the Indian Medical Association. As turmeric has been used by all Indian families as a traditional wound healer in India for

thousands of years for healing wounds and rashes.

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Inventors decided to file a Objections to the re- examination results.

The powder and paste form of Turmeric had different physical properties which

helps wound healing, i.e. bio-availability and absorbability, and

therefore, one of the ordinary skills in the art would not expect, with any

reasonable degree of certainty, that a powdered material would be useful in the

same application as a paste of the same material.

oral administration was available only with honey and honey itself was considered

to have wound healing properties.

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In the second re-examination It was observed that the paste and the powder forms were equivalent for

healing wounds in view of the cited material by CSIR The examiner rejected all the claims once again and up held the contentions

raised by CSIR and revoked the patent. Observations:

The turmeric case was a landmark case as it was the first time that a patent based on the traditional knowledge of a developing country had been successfully challenged.

The legal costs: US $10,000 ( Govt. of India)

6

Neem

NGO with Indian farmers and EPO

7

Neem (Azadirachta indica)

Neem extracts used against hundreds of pests and fungal diseases that

attack food crops; the oil extracted from its seeds is used to treat colds

and flu; and mixed in soap, it is believed to offer low cost relief from malaria, skin diseases and even meningitis.

In 1994 the EPO granted patent No. 0436257 to the US Corporation W.R. Grace and USDA for a “method for controlling fungi on plants by the aid of a hydrophobic extracted neem oil”.

In 1995 a group of international NGOs and representatives of Indian farmers filed a legal opposition against the patent.

8

Neem (Azadirachta indica)

They submitted evidence that the fungicidal effect of extracts of neem seeds had been known and used for centuries in Indian agricultural to protect crops, and thus was the invention claimed in EP257 was not novel.

In 1999 the EPO determined that according to the evidence “all features of the present claim have been disclosed to the public prior to the patent application… and [the patent] was considered not to involve an inventive step”.

The patent was revoked by the EPO in 2000.

9

To Avoid Costly Battles

10

India succeeded because proved these were part of traditional Indian knowledge.

Traditional Knowledge - Protection

Defensive protection

Defensive Disclosure : Developing TK databases that may be used as evidence of prior art to defeat a claim to a patent on such TK

Prior informed consent : Permission to use resource or knowledge

IP rights over TK are not given to parties other than the customary TK holders

Positive protection :sui generis

Access and benefit sharing

11

Traditional Knowledge Digital Library (TKDL)

Government of India has taken steps to create a TKDL

8 years Meticulously translating ancient

Indian texts Compiling the information into a

database Details on 200,000 treatments. IPC: TKRC ( Traditional Knowledge

Resource Classification) International acceptance

Help patent examiners for easy retrieval of traditional knowledge related information

Avoiding possibilities of granting patents to unoriginal inventions

Review process of patents already granted in light of TKDL database would help in cancellation of patent

To check against “bioprospectors”

12

Basmati Case

Ground : Geographical indications

Basmati Case

Basmati Case was an eyeopener for India, in the sense that it brought into spotlight an instance of gross exploitation of developing county rights.

Geographical Indications are relatively new instruments which are gaining rapid popularity in the trade

and economic scenario, which recognize the heritage of a country in certain specialized goods and seek to protect the same.

GI indicates the special protection that particular goods enjoy by the virtue of their geographical origin which renders them special and peculiar quality.

Basmati Case

THE FACTS Basmati:

Originally from India and Pakistan

Basmati became a controversial ‘issue’ after RiceTec, a Texas-based company, in 1997, patented some types of rice they developed as “American basmati”.

RiceTec Inc, trying to enter the international Basmati market with brands like “Kasmati” and

“Texmati”.

Ultimately, the company claimed to have developed a new strain of aromatic rice by interbreeding basmati with another variety, as Texmati or American Basmati.

Issued the Patent number 5663484 on Basmati rice lines and grains on September 2, 1997.

Basmati Case

Objection: by two Indian nongovernmental organizations (NGOs) — Centre for Food

Safety, an international NGO that campaigns against biopiracy, and the Research Foundation for Science, Technology and Ecology, an Indian environmental NGO who filed legal petitions in the United States.

The Centre for Scientific and Industrial Research also objected to it. They sought trade protection for basmati rice of the Indian subcontinent and

jasmine rice of Thailand. They demanded amendment of U.S. rice standards to specify that the

term“basmati” can be used only for rice grown in India and Pakistan, and jasmine for the Thai rice.

The Indian government, after putting together the evidence, officially challenged the patent in June 2000.

Basmati Case

THE ISSUES the answers to which are hoped to be answered through the emerging law of

patents and geographical indications. Some of the major issues are: Whether the term ‘basmati’ is a generic one to describe aromatic rice, or

does it refer specifically to the long aromatic rice grown in India and Pakistan?

Whether the strain developed by RiceTec is a novelty?

Whether RiceTec is guilty of biopiracy?

Whether US government’s decision to grant a patent for the prized Basmati rice violates the International Treaty on Trade Related Intellectual Property Rights (TRIPS)?

Whether the basmati patent should be revoked in the light of protests from India?

Basmati Case

Importance of Basmati in India and Pakistan Economy Rice is an important aspect of life in the Southeast and other parts of Asia.

More substantively, Indian farmers export $250 million in Basmati every year and U.S. is a target market

the main aim for obtaining the patent by RiceTec Inc. is to fool the consumers in believing there is no difference between spurious Basmati and real Basmati.

Basmati Case

theft involved in the Basmati patent is, a theft of collective intellectual and biodiversity heritage on Indian farmers, a theft from Indian traders and exporters whose markets are being stolen by RiceTec

Inc., and finally a deception of consumers since RiceTec is using a stolen name asmati for rice

which are derived from Indian rice but not grown in India, and hence are not the same quality.

RiceTec Inc. had attempted to sell its long-grain rice in Europe under such brand names as

‘Texmati’ and ‘Kasmati’ but not as Basmati. However, if the patent is not revoked, RiceTec Inc., can now sell its rice under the

brand name Basmati which will definitely cut into India’s and Pakistan’s global market share, especially as the rice grown in the US could be sold cheaper than the Indian and Pakistani varieties.

Basmati Case

CASE ANALYSIS RiceTec has got a patent for three things:

growing rice plants with certain characteristics identical to Basmati,

the grain produced by such plants, and

the method of selecting rice based on a starch index (SI) test devised by RiceTec,

The patent was challenged on the fact that the plant varieties and grains already exist as a staple in India.

5 75 percent of U.S. rice imports are from Thailand and that the remainder is from India and Pakistan and both varieties are rice that cannot be grown in the United States.

The legal theory is that the patent is not novel and for an invention that is obvious, being based on rice that is already being imported in the United States, therefore it should not have been granted in the first place.

Basmati Case

India’s attorneys to challenge the use of the term ‘basmati’ in conjunction with the patent and in marketing

of the rice.

Such use of the term creates confusion as to geographic origin and usurps the goodwill and recognition established with basmati rice grown and sold from India.

Re-examination: As a result of the re-examination application filed by the Indian government, RiceTec

agreed to withdraw several of the claims.

In January 29, 2002, the United States Patent and Trademark Office issued a Reexamination Certificate canceling claims 1-7, 10, and 14-20 (the broad claims covering the rice plant) out of 24 claims and entered amendments to claims 12-13 on the definition of chalkiness of the rice grains

Basmati Case

Trademark law: could also be a basis for challenging the use of basmati. RiceTec and to prevent it from marketing basmati rice in a way that

creates confusion with the Indian product.

But, in order to be successful on such a claim, the Indian government would have to show likelihood of confusion among consumers.

RiceTec did not trademark the term ‘basmati’ and it has been careful in marketing its product so as not to use the term basmati as an indication of source. The Indian government could argue that this use of the term basmati is what

creates confusion among consumers. The term basmati need not be federally registered as a trademark for India to raise the claim.

Basmati Case

Basmati, the word means fragrant and hence describes a major attribute of the product. .

Descriptive marks are protected only if they have secondary meaning, that is, the term makes the ordinary consumer recognize the source of the product as opposed to the product itself.

In this vein, RiceTec could also argue that the term basmati has become a generic term for a particular category of rice and

hence cannot be protected.

However, now it is much a settled position that geographical indicators need not necessarily indicate the place of origin, it could signify the product itself as long as it is known to possess certain qualities by the virtue of its belonging to certain place.

Basmati Case

If India loses the fight against RiceTec, the issue remains of what India can strategically do to protect its rights in basmati rice.

U.S. trademark law does not offer a successful avenue for India.

The TRIPS agreement expressly protects ‘indicators of geographic origin’ and permits legal recourse through the WTO process to discontinue use of misleading geographic indicators.

The problem with relying on TRIPS is the ‘basmati’ is not a geographic indicator; the word literally, describes the scent of the rice, not its geographic source.

Basmati Case

One tactic that the government has recently pursued is to enact its own law granting protection to marks that indicate geographic origin.

Basmati is arguably protected under these recently enacted provisions. One argument that the Indian government made in challenging RiceTec’s

patent is that basmati should be treated like ‘champagne’ and ‘burgundy’.

The TRIPS agreement expressly forbids trademark protection for geographic indicators as applied to wine and spirits. The United States has amended its trademark law to reflect this prohibition

Basmati Case

Basmati originated in Punjab which spans areas of both India and Pakistan. This explains why its only grown in those two countries. Punjab is one of the smallest states in India. However, its geology that is, its deep and fertile soils as well as its exceptional climate has a far reaching impact on India's economy.

Basmati is viewed as a cultural heritage

This further supports the argument that Basmati has existed in India and Pakistan for centuries and as such cannot be patented by the US.

Novartis (Glevec)

Pregrant opposition and IPA 3 (d)

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Dr.B.S. Kuchekar 2008 28

Novartis (Glevec) Case

Novartis Filed patent for Imatinib mesylate in India (1998) (Chennai) Patented in 35 countries Treatment of Chronic Myloid Leukomia Temporary monopoly was granted for 5 years (EMR) At that time, India did not yet grant patents on medicines After expiry period Cipla, Hetero, Natco, and Ranbaxy started production of

Generic version. Cost of treatment : Per patient/month in India

Novartis- Rs.1,20,000 Cipla, Hetero, Natco, Ranbaxy- Rs.8000

In Nov 2003, Novartis again applied for EMR for a period of five years.


EMR The granting of EMR was a TRIPS obligation for countries like India, which did

not grant patents for pharmaceutical products before 2005 (subject to a number of conditions).

Producers of generics were forced to withdraw the production and sale of generic versions of the drug in India and other developing countries.



After 2005, when the Indian patent office began examining pharmaceutical product patent

applications,

EMRs would either be replaced by patents (if granted) or cancelled (if patents were rejected).

The Cancer Patients Aid Association filed an opposition on behalf of cancer patients in the Chennai patent office.




Chennai Patent Office : January 2006 Rejected Novartis' patent application on the grounds that the application

claimed 'only a new form of a known substance.'

It not only prevented a patent monopoly until 2018,

but also automatically cancelled the EMR



On 17 May 2006, Novartis filed two sets of cases in the Chennai High Court.

The first case Challenges the order of the Chennai Patent office, which rejected the Gleevec

patent application of Novartis, following a pre-grant opposition by the Cancer Patients Aid Association.

The second case Challenges the constitutionality of section 3(d) of the 2005 Indian Patents Act,

which was specifically introduced by the Indian parliament as a safeguard against the misuse of the product patent regime.



Novartis in its petition is claiming that the section is not in compliance with the TRIPS Agreement and hence should be declared unconstitutional.


The High Court in Chennai dismissed the writ petition challenging the

constitutionality of Section 3(d), and deferred to the World Trade Organization (WTO) forum

to resolve the TRIPS compliance question. In the separate Glivec patent appeal,

Novartis is petitioning the High Court in Chennai for a new technical member of the Intellectual Property Appellate Board (IPAB).

Novartis disagree with the appointment of the former Controller General of the Indian Patent Office to the IPAB.

The Government asked for additional time to submit their arguments.

The next hearing date on this matter was set for October 8, 2007.




The Madras High Court, which heard Novartis petition against Intellectual Property Appellate Board (IPAB)'s decision to allow the former Patent Controller General S Chandrasekharan as the IPAB technical member to hear the Novartis plea for cancer drug Glivec, has agreed to consider removal of Chandrashekharan.

The government suggested a revised approach consisting of a chairman and a vice-chairman. The court has invited written comments from both sides and will reconvene on October 22, 2007 to make a final decision.

Roche Products V/s Bolar Pharmaceutical Co. (Fed. Cir. 1984)

Ground: Work on patent product for scientific use is not infringement

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Roche Products V/s Bolar Pharmaceutical Co.

Roche got patent for Flurazepam, API of ‘Dalmane’

which expires on Jan. 1984. In early 1983, Bolar decided with interest to market a generic

drug product equivalent to Dalmane after expiry of that patent.


Approval of an equivalent of an established drug can take more than 2 years.

Bolar, not waiting for the patent to expire, started to obtain federal approval to market its generic version of Dalmen.

In mid-1983, Bolar obtained the patented drug from a foreign manufacturer to make capsules and carry out the stability, dissolution rate,bio-equivalence and blood serum studies necessary for a New Drug Application to the FDA.



Roche filed a complaint of infringement in the District Court against Bolar

Making, using, or selling any patented invention without authority constitute Infringement of patent.

Bolar’s intended “experimental” use is solely for for business purpose and not for amusement or to satisfy curiosity or for philosophical inquiry.

Bolar infringes Roche’s Patent.



However as per IPA Amendment May 2003, Use of a patented product to experiment the scientific study, does not constitute an infringement.

BOLAR PROVISION:(Research exemption)

It enables a manufacturer of generic drugs to use patented invention to obtain marketing approval without the patent owner’s permission before the patent expires.


Lipitor Case (Pfizer Vs Ranbaxy)

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Pfizer V/s Ranbaxy

Action was brought by Plaintiff, Pfizer against Defendant, Ranbaxy for infringement of U.S. Patent No.4,681,893 and U.S. Patent No. 5,273,995.

Pfizer owned the ‘893 and ‘995 patents pertaining to Atorvastatin.‘893 for acid atorvastatin –Expiry 2011‘995 for salt atorvastatin calcium (Lipitor) –2015

Ranbaxy filed ANDA


Complaints from Pfizer against Ranbaxy alleging that Ranbaxy’s proposed ANDA product infringes the ‘893 and 995 patents.


US 5,273,995

Independent claim 1 covers atorvastatin acid

and its salts

Dependent claim 2 covers atorvastatin

lactone

Dependent claim 6 claims hemicalcium salt of compound of claim 2


In response to Pfizer’s complaints, Ranbaxy alleges-

It does not infringe either the 893 or 995 patents. It also challenges the validity of the patent term extension

granted by PTO for the ‘893 patent. It contends that the asserted claim 6, is invalid for double

patenting, obviousness and anticipation. It also contends that the’995 patent is unenforceable.


Court Decision US 4,681,893

Court Decision:1. Pfizer had ample data to support the claims it made to the

PTO for US 4,681,893 which was scientifically sound.2. Instances of non-discloser cited by Ranbaxy are sufficient to

demonstrate an intent to deceive the PTO.3. Also Ranbaxy has not met its burden of establishing

inequitable conduct.


Court concludes:

Pfizer has established that Ranbaxy’s ANDA product literally infringes the ‘893 and ‘995 patents,

Judgment:

In favor of Pfizer and against Ranbaxy. (Dec.23,2005)

Ranbaxy appealed in court of appellate i.e. Federal court. Ranbaxy partially own the case.


Pfizer V/s Ranbaxy Court Decision on Infringement of - US 5,273,995

Independent claim 1 covers atorvastatin acid

and its salts

Dependent claim 2 covers atorvastatin

lactone

Dependent claim 6 claims hemicalcium salt of compound of claim 2

Practically hemicalcium salt (claim 6) of atorvastatin lactone (claim 2) is not possible, instead hemicalcium salt is possible for atorvastatin acid (claim 1), so court held patent is invalid due to improper claim dependency and drafting


Mar 2008: Presently Pfizer has settled All Lipitor Patent Litigations with Ranbaxy worldwide

Roche –Cipla :Erlotinib Hydrocloride

Ground: 3(d), mailbox application


Erlotinib Hydrocloride Tarceva, a lung cancer drug, Hoffman La Roche Ltd.

Granted a patent for erlotinib in India in September 2007.

Soon after, Roche started selling the drug for Rs 4,800 ($122) a tablet.

Despite this, Cipla Ltd of Mumbai launched a generic version of Tarceva – erlotinib – the active ingredient in the

drug – last year.

While launching the drug, Cipla was quoted as saying that they intended to launch their own version of the drug at far lesser price – Rs1,600 ($41) a tablet.


Roche dragged Cipla to the Delhi High court,alleging that Cipla infringed their patent rights over Tarceva, Roche sued Cipla before Delhi High Court claiming that Cipla’s generic product Erlocip

violates former’s Indian Patent IN196774 claiming “Erlotinib Hydrocloride

applied for a temporary injunction.

During hearings, Cipla counterclaimed that the patent was invalid and should be revoked.

The trial judge, refused to grant an interim injunction on the ground that since Cipla was selling the drug

at 1/3rd of the price of Roche, an injunction would have meant lack of affordable access for a large number of cancer patients in India.

Therefore, "public interest" demanded that no injunction (restraining order) be granted


Division Bench: Roche’s subsequent appeal Failed miserably when not only did the bench uphold the findings of Trial Judge

but also imposed costs on Roche for suppression of material patent information about Roche’s later filed application in India (IN/PCT/2002/00507/DEL) which was specifically on Polymorph B of Erlotinib Hydrocloride (‘507 application was rejected in 2008 following the opposition filed by Cipla primarily on Section 3d.

Cipla argued that Tarceva corresponds to Polymorphic Form B of active ingredient Erlotinib Hydrocloride

(claimed in ‘774 patent) and

that it is Form B which is more stable and suitable for solid oral dosage form than the compound disclosed in ‘774 patent comprising a mixture of Forms A and B.

The interesting part was that the claims were not even construed during the trial even once.


Supreme Court Roche’s subsequent appeal before the Supreme Court (SC) challenging the

order passed by the division bench got dismissed on August 29, 2009.

Key reason for the dismissal was the ongoing trial at the Delhi High Court and SC ordered the ongoing trial be expedited


Cipla claimed that : erlotinib (Tarceva) is a derivative of an earlier substance called gefatinib, and

therefore should not have been granted a patent, unless increased efficacy can be proved.

The litigation concerned Indian patent number 196774, which was issued against a mailbox application dated March 1996.

In March 1999 the Indian government amended its patent law to allow companies to file mailbox pharmaceutical patent applications prior to the launch of India’s product patent regime.

The law applied retrospectively from January 1 1995 and the Patent Office began to examine them in 2005, after the law was changed to allow product patents to be issued for pharmaceuticals.

The trial judge refused to grant an interim injunction on the ground that since Cipla was selling the drug at 1/3rd of the price of Roche, an injunction would mean impeding affordable access for a large number of cancer patients in India. Therefore, “public interest” demanded that no injunction

(restraining order) be granted.


However, a High Court bench vacated its interim order by which Cipla was restrained from exporting the drug to other countries in which La Roche has patent rights.

The Delhi High Court dismissed the plea of the Swiss company saying that the Indian company

should be restrained from manufacturing and selling the generic drug till the issue of patent rights was decided through litigation.

The Swiss company had approached the Division Bench of the High Court after a single Bench had dismissed its plea to restrain Cipla.

The Court also imposed a cost of Rs five lakh (US $ 10,000) on Roche.


The Indian Supreme Court dismissed the special leave petition filed by Roche on a generic version of its

erlotinib (Tarceva) from Cipla, challenging the order passed by a the division bench of the Delhi High Court in April 2009.


India’s patent law allows companies to oppose patents both before and after grant.

It has to remembered that Section 3(d) of India’s Patent Act, which was challenged by Novartis in the courts last year, was also the feature in the case.

Section 3(d) restricts what can be patented.

In particular, the section states that salts and other derivatives of known substances “shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy”.

Roche Vs Natco : Erlotinib Hydrocloride


Natco's arguments: that Roche does not manufacture the product in question; that the patent is invalid; that Natco does not infringe; that the Division Bench order of the Delhi HC (in the Roche-Cipla case) is

binding in this case; and that there is material suppression of facts. Roche's product (the anti-cancer drug Tarceva) did not conform to the

patent specification they were claiming infringement of. By extension, Natco suggested that Roche's patent was effectively a "paper

patent", and not capable of being worked. the patent had to be manufactured in order to be worked in India.

The second line of argument was that since neither Tarceva (Roche's product), nor Erleva (Natco's product) could be associated with the patent in question, there could be no infringement.

http://spicyipindia.blogspot.com/2009/08/breaking-news-supreme-court-dismisses.html


Expectedly, Natco then drew attention to the Roche-Cipla case, where Roche had been denied an interim injunction by the Division Bench of the Delhi

High Court (mentioned above).

In view of the DB order, it would be inconsistent to suggest that the same patent could be considered invalid against one party (Cipla), and not invalid against others.

Natco also reiterated the "public interest" argument that had come up in the DB order, as also that the same order had noted that a credible challenge had been raised against Roche's patent.

Surely enough, and with an evident reference to Roche's previous arguments, Justice VK Shali, who is hearing the case, pointed out that the Supreme Court order in the Roche-Cipla case had reiterated the general principle that interim orders were not binding,


Natco then proceeded to tackle Roche's reference to the pre-grant opposition and the compulsory licensing application that followed.

Readers will recall Roche's contentions, among others, that Natco was estopped, and that res judicata came into play.

Natco responded, not surprisingly, that the pre-grant was neither final nor binding, and that Indian patent law allowed anyone to question the validity of a patent at any stage. It also argued that the fact that Natco's not filing a post-grant opposition was inconsequential.


Natco then went into the meatier aspects of the patent and the product, arguing variously as follows – That Roche had suppressed material facts, in not disclosing the composition

or form of their product. Roche was aware that their product was in fact the "Polymorph B" form of the

compound claimed in the suit patent. Natco claimed that Roche had failed to bring to the attention of the court that each

Polymorph of a compound could exhibit different physical properties- which could be drastically different from the main compound.

That the US equivalent of the Indian patent US 5747498 was for "a mixture... a formula". And to highlight that the patent in question was not the same as Tarceva, Natco's

senior counsel referred to the Polymorph B application in the United States and India.


Natco then went into the meatier aspects of the patent and the product, arguing variously as follows – That the Indian patent specification made no mention that the patent cured

Non-Small Cell Lung Cancer. This was contrary to the Polymorph B application (and the patent as granted in

the US) which made specific reference to the same.


Natco then went into the meatier aspects of the patent and the product, arguing variously as follows – That the Division Bench had specifically asked Roche to disclose X-ray

diffraction data.

On its part, Natco submitted affidavits on such data to show that both their Erleva and Roche's Tarceva were the Polymorph B form of the patent in question, thus confirming that Roche did not manufacture the patent, and that there could be no infringement.

With that, the matter has now been adjourned and been made a part heard matter and will be heard by Justice Shali on the 16th of July 2010

Roche Vs Cipla: Valganciclovir

Gorund: 3(d), postgrant opposition


Valganciclovir for the treatment of active cytomegalovirus (CMV) retinitis that occur in people

living with HIV.

an ester prodrug of ganciclovir.


The contentious Section 3(d) of India’s Patent Act, last year, Section 3(d) restricts what can be patented.

In particular, the section states that salts and other derivatives of known substances “shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy”.


Pregrant opposition Several NGOs involved in anti-HIV campaign and human rights groups were

opposing the granting patent protection to valganciclovir.

The Chennai Patent Office did not hear the opposing arguments of public interest groups including the

Indian Network for People Living with HIV/AIDS (INP+) and the Tamil Nadu Networking People with HIV/AIDS (TNNP+), and went ahead granting the patent for valganciclovir in 2007.

The Patent Office granted a patent to Roche for valganciclovir (Valcyte) in June 2007.


The Madras High Court in Chennai The public interest group approched court.

In December 2008, the Madras High Court in Chennai decided to set aside Roche’s patent until these arguments could be heard.

Supreme Court Following the rejection of the pre-grant opposition by the patent office, the

public interest groups approached India’s Supreme Court.

The Supreme Court directed the groups to join the post-grant opposition proceedings that were already taking place through oppositions filed by generic companies and the Delhi Network of Positive People (DNP+).

Roche, however, challenged DNP+.


The Indian Patent Office has now recognised only the validity of one of the process claims made by

Roche and

determined that the claims for a product patent on valganciclovir were invalid.

It has also held that patients groups can file post-grant oppositions.


Cost Valganciclovir is also used for post operative treatment for patients who have

received an organ transplant.

A patient would require 264 oral doses given over four months for the effective treatment of cytomegalovirus (CMV) infection.

This could be a heavy burden for the patient as the overall cost of the treatment come reach upto Rs 2,74,560 per patient.

Cipla Launched India in September 2008, even while the drug enjoyed patent

protection in following the grant of patent in 2007.


India’s patent law allows companies to oppose patents both before and after grant.

Significantly, Indian Patent Office, Chennai’s decision to revoke valgancicyclovir patent


The Indian Patent Office at Chennai, in a decision released on April 30, 2010, has set aside the patent granted to Roche for valganciclovir, after declaring

that the drug lacked inventive step that qualifies one new product or inventions to secure patent protection in India.

Ganciclovir is a known compound and hence valganciclovir did not have an inventive step.

In addition, valganciclovir did not satisfy the requirement of showing increased therapeutic efficacy as required under section 3(d) of the patent law.

(Pegylated interferon alfa-2a)

Roche Vs Wockhardt

Ground: 3 (d)

Roche Vs Wockhardt

Roche and Wockhardt – Roche got its first product patent in India in 2006 for Hepatitis Drug Pegasys.

(Pegylated interferon alfa-2a).

Its first and forthcoming patents all were being attacked by Indian Generics (not to forget various NGOs) whether through series of oppositions filed or counter attacking to Roche’s suits of infringement.

Post Grant opposition India’s first post grant opposition was filed by Wockhardt and a Mumbai based

NGO for “IN198952” on Pegasys attacking its validity claiming it to be non-inventive and

not satisfying Section 3d (the section which has become the most controversial sections of Indian Patent Act

Roche Vs Wockhardt

It was argued that the claimed invention, the branched pegylated form of interferon alfa 2a did not satisfy the patentability criteria

under Indian law as Pegasys involves combining interferon with polyethelyene glycol (PEG) which helps the interferon to remain in the bloodstream, and also that the technology of combining interferon and other biologically active proteins with PEG had been known for years prior to Pegasys patent.

In light of this, the counsel put forward that there was no inventive step and was obvious to a person skilled in the art.

Further, they alleged that Roche’s ‘invention’ is at most a ‘mere admixture’ of known substances and thus not patentable under section 3(e) of the Patents Act 1970, and is just a ‘new form of a known substance’ and not patentable under section 3(d) of the Act.

Roche Vs Wockhardt

Roche and Wockhardt – Interestingly, Assistant Controller T.V. Madhusudan (in March 2009) ruled

against the recommendation of Opposition Board to revoke the patent and held the patent to be valid.

Roche successfully cleared the “enhanced efficacy” test in the Section 3d of the Indian Patent Act (including the novelty and obviousness tests).

Roche Vs Wockhardt

Section 3d allows a novel derivative of a known compound only when such derivative

shows enhancement in known efficacy of a known compound.

The efficacy is defined as therapeutic efficacy as per Madras High Court decision in Novartis Gleevec Case.

Interferon known compound and

known efficacy is its antiviral and anti proliferative activity and

the experimental results in the patent showed that there is indeed enhancement of therapeutic efficacy which resulted in Roche’s victory.

Gilead Vs Cipla -Tamiflu


Gilead oseltamivir, Tamiflu, An antiviral drug

used in the treatment and prophylaxis of both Influenzavirus A and Influenzavirus B. Like zanamivir, oseltamivir is a neuraminidase inhibitor. It acts as a transition-state analogue inhibitor of influenza neuraminidase, preventing progeny virions from emerging from infected cells.

Oseltamivir was the first orally active neuraminidase inhibitor commercially developed.

It is a prodrug, which is hydrolysed hepatically to the active metabolite, the free carboxylate of oseltamivir (GS4071).


Cipla Filed pregrant opposition

opposed granting of patents rights to Gilead’s Tamiflu did not have inventive step – a pre-requisite for products to gain patents in India.

Tamiflu is only a derivative and pharmaceutically acceptable salts, solvates and derivatives, dissolved enantiomers and purified diastereomers in the claimed composition are clearly not patentable under section 3(d) of the Indian Patent Act.


The Patent Office in Delhi decided against Gilead as it found that the applicant (Gilead) failed to provide any

supportive evidence in the specification by means of comparative data or by way of examples which would have supported the inventive merit of oseltamivir.

the decision it found anti-influenza agent oseltamivir to fall within the provisions of section 3(d) and

not patentable.

The Delhi Patent Office particularly relied on the decision of European Board of Appeal (T-0133/01) stating that alleged but unsupported advantages cannot be taken into consideration in respect of the determination of the problem underline the claimed invention.


Pre-Grant Opposition in India The provision of Pre-Grant Opposition has been incorporated as one of the provision for opposing

the grant of a new patent into Indian Patent Laws, which came into practice on January 1,2005.

Opposition to grant of patent is a provision for hearing at pre-grant opposition stage has been made in the rules.

A pre-grant opposition can be filed for an application for a patent which has been published but a patent has not been granted.

Any person may, in writing, represent the opposition to the controller against the grant of patent within a minimum period of 6 months, from the date of publication is provided for making representation as against the present period of 3 months, for filing pre-grant opposition.

The grounds of pre-grant opposition in the Ordinance were novelty, inventive step and industrial applicability, non-disclosure or wrongful mentioning of source and geographical origin of biological material and anticipation of invention by knowledge, oral or otherwise, available in public domain.


In October 2005, the Indian drug company Cipla announced their plan to begin manufacture of generic oseltamivir without license from Roche.

Patent laws allow governments to authorise supply from generic companies, subject to remuneration to patent owners to address public health problems, including emergencies.

However, Roche wanted to remain the sole supplier of the drug.

Cipla argued that it can legally sell oseltamivir to India and 49 other developing countries.


As the dispute continued, Roche granted a sub-license to the Hyderabad-based Hetero Drugs for the

production of oseltamivir (Tamiflu), in December 2005.

The agreement with Hetero is focused on providing oseltamivir for government pandemic use and will have an immediate effect on the availability in India and developing countries – both directly and through further agreements with local companies.

However, Cipla received marketing approval from the drug controller-general of India in January 2006.

The drug will be priced at about Rs 1,000 per strip of 10* 75 mg tablets – less than half the current Tamiflu market price of $60.

Glilead Vs Cipla -Tamiflu

The Indian Patent Office has denied Gilead Science Inc. patent rights for its anti-influenza drug oseltamivir phosphate marketed as Tamiflu, in India.

SB and Fujimoto

Ground : Import of Patented Product

88


SmithKline Beecham(SB) V/s Fujimoto Pharmaceutical Co.

SB had filed a process patent in Japan on Cimetidine in September 1973. Granted in 1981 and was valid up to Sept 1993.

In December 1986,Fujimoto imported the infringing product from Yugoslavia and sold 68,000 tablets in Japan, Fujimoto also manufactured a generic version of Cimetidine


SB claimed that Fuimoto had infringed their patent from Dec. 1986-Sept. 1993

Fujimoto argued that their process was not covered by the SmithKline patent

The Judge found Fujimoto liable for patent infringement. (Tokyo District Court,1998.)

SmithKline Beecham(SB) V/s Fujimoto Pharmaceutical Co.


The Court awarded SB and SBS

Yen 500 million($4.2 million) in royalties and

Yen 2.5 billion($21 million) in lost profit based on a 15% profit rate.

SmithKline Beecham(SB) V/s Fujimoto Pharmaceutical Co..

Sumesh Reddy-NALSAR Visiting Faculty

92

THE UPJOHN COMPANY v. MOVA PHARMACEUTICAL CORP.,

Doctrine of Equivalence

The Patents

Upjohn United States Patent No. 4,916,163

(the '163 patent)-

anti-diabetic pharmaceutical composition containing at least 70% by weight of spray-dried lactose as the preponderant excipient.

Active ingredient- micronized glyburide.

Improvements- the excipients comprise a glidant, lubricant and disintegrant.

MOVA Active Ingredients : Micronized

glyburide

Inactive ingredietsn: spray-dried lactose as an excipient.

But contains 49% by weight of spray-dried lactose and

46.3-49.1% of Starch 1500 (pregelatinized corn starch).


93


94

Issues: Infringement.

Whether MOVA infringes under the doctrine of equivalents.

The court found that there were differences between the excipient behavior of Starch 1500 and

spray-dried lactose,

particularly that Starch 1500 operates by disintegration instead of dissolution. Starch 1500 disintegrates, breaks up the tablet and releases the active ingredient

and the active ingredient is dissolved

Spray-dried lactose tablet- the drug is released as the lactose dissolves

Issues: Validity

The obviousness arguments and the prior art examined

The Rothe Patents. These patents showed

micronized glyburide and, as the pharmaceutical excipient, ordinary lactose.

Company was able to show that using lactose which is not spray-dried does not yield a formulation which is easily and readily manufacturable,"

The Simpson Patent a specific example of spray-

dried lactose as the excipient with a micronized anti-diabetic drug (2,6-di-t-butylamino-3-formyl-4-methyl-pyridine)

[micronized anti-diabetic drug] 100 mg Gum tragacanth 10 mg Lactose (sprayed-dried) 197.5 mg Corn starch 25 mg, Talc 15 mg Magnesium stearate 2.5 mg This formulation contains 56.4% spray-

dried lactose


95


96

Simpson teaches that

"a typical dosage unit may contain typically 25-500 mg of a compound of Formula I, or a pharmaceutically acceptable acid addition salt”

All that Upjohn has done is to substitute 25 mg for the 100 mg in the Simpson

example, keeping all other ingredients constant. This change produces a formulation containing 72%

spray-dried lactose.


97

The court said….

“That it would not have been obvious to make this change when the formulation contains glyburide, a product that is not shown in the Simpson reference, by greatly reducing the amount of active ingredient.”


98

Lieberman & Lachman

"sprayed-dried lactose is an effective direct compression filler when it makes up the major portion of the tablet (more than 80 percent)."

segregation and aggregation problems arise during direct compression of formulations containing micronized drugs .

using this high percentage of spray-dried lactose with a micronized active ingredient.

teaches away from direct compression by suggesting use of wet granulation to avoid these problems.

Does not therefore represent prior art.


99

The Johnson Article.

MOVA alleged that Johnson teaches the blending with spray-dried lactose of a partly micronized, partly non-micronized drug.

The article describes an average tetracycline size of 10m, therefore a significant proportion of the drug was micronized.


100

Court rejected the prior art of Johnson.

There is no evidentiary support for the MOVA argument that a significant portion of the tetracycline was micronized.

MOVA does not suggest that either the pharmacologic effect or the physical properties of tetracycline is similar to glyburide.


101

Conclusion

The federal court affirmed the judgment of non-infringement and reversed the judgments of invalidity and unenforceability.


102

Learning

• The importance of the application of the doctrine of equivalents in an infringement analysis relating of a formulation patent

• When a formulation patent consists of a combination of two or more elements, it is important to substitute at least one element that performs the same function in a different way

• The case is a good example of the way in which the court applies an obviousness analysis to a series of prior art references

• Gives you some idea of what a prior art reference should teach or contain in order to render a patent claim obvious

IPR Case

Dr. Sanjay Boldhane

Bayer Vs Cipla –Nexavar (Sorafenib)

Status: 18Apr2010


Bayer, which holds a 2007 patent for Nexavar in India The Bayer has claimed that by launching a generic version of the drug, Cipla

has infringed on its Indian patent no. 215758.

Unfortunately the IPIRS system on the Patent Office website has failed to display any information on this patent.

Bayer argued that Cipla’s generic sorafenib, which is branded as Soranib, if examined and granted marketing rights, will be seen as a spurious drug as per the Drugs and Cosmetics Act.


Round I of the litigation: 2008 :Delhi High Court

a writ requesting directions to the Drug Controller General of India to deny Cipla's request for marketing approval to launch a generic version of Bayer's patented drug - 'Nexavar'.

That round of litigation ended in a disaster with Bayer losing spectacularly before both the Single Judge and the Division Bench of the Delhi High Court.

dismissed the writ petition filed by Bayer Corporation and asked the company to pay costs amounting to Rs 6,75,000 in equal shares to the Union of India and Cipla.


Division Bench of Delhi High Court Bayer again moved a petition to the divisional bench of Delhi High Court

contesting that since it holds the patent for Nexavar (sorafenib tosylate) which is valid for 20 years, DCGI cannot give marketing approval for Cipla’s generic version.

Indian patent law provides the patent holder exclusive marketing rights for 20 years with no competition from generic companies.

Bayer argued for the need to bring in in the concept of linking patent grants under Section 48 of the Indian Patents Act to marketing approval of the drugs on Section 2 of the Indian Drugs & Cosmetics Act.

Bayer also appealed to make it distict that “generic drugs can only be legally produced for drugs which are free of patent protection”.


Cipla, the grant of marketing approval by DCGI does not amount to infringement of

the patent and such violations, if any, is alleged which needs to be established in a court of law in accordance with the provisions of Indian Patent Act.

Moreover, the drug regulator is not a competent authority to decide on complex matters involving patents.

Section 107A of the Patents Act clearly exempts from patent infringement any of acts of making, using or even selling a patented invention, in so far as such acts are necessary to obtain information for the filing of a drug regulatory application before the authority.


DCGI The publicly funded drug regulator cannot be used to further the enforcement

of the private rights of a patentee.

DCGI, on the otherhand, expressed his office’s inability to deal with complex patent issues pointing out lack of institutional expertise.

Indian Pharmaceutical Alliance, the umbrella body representing the leading Indian companies, also supported the stand.

The Delhi High Court upheld its earlier ruling saying that it did not find “any ground having been made out to reverse the well reasoned judgment of learned single Judge in which we fully concur.”

DCGI powers and jurisdiction are circumscribed by the Drugs and Cosmetics Act 1940, and not by the Patents Act, the HC ruled, dismissing the petition.


Cost Cipla said it would to launch the generic version of sorafenib within two months

at less than half the price of Bayer’s Nexavar.

Nexavar costs Rs 2.85 lakh for a monthly dose of 120 tablets.

Cipla launched its generic versions of anti-cancer drug erlotinib, patented by Roche and branded Tarceva, even after the Swiss company was granted product patent in India.


25Mar2010 Bayer, however, stated that it could appeal against the decision at the

Supreme Court expressing the companies decision to defend the patent vigorously.

Indian Supreme Court has, however, rejected a plea from German drug giant Bayer AG seeking to block the marketing approval of a generic version of its patented kidney cancer drug Nexavar (sorafenib) by Cipla.

The Supreme Court only issued notices and refused to grant any interim order as sought by Bayer AG to stop Cipla from launching its drug until the court decides the case, reports said quoting legal experts involved in the case.

Product Approval and Patent Linkage

Bayer

Bayer patent-linkage plea

Petition filed by Bayer seeking introduction of patent linkage system in India. In August, 2009, a single-judge bench of the Delhi High Court

had rejected Bayer’s attempt to bring patent linkage — a system that can delay the entry of low-cost generic

drugs into the market by making the drugs controller general of India (DCGI) act like patent police and

refuse marketing approval to generics if the innovators hold a patent in India.

Bayer patent-linkage plea

Nowhere in Trips is there a reference to an obligation to link patent protection and drug registration,” says an international patent law expert. the DCGI should not be asked to look into the patent status of drugs as the DCGI and

Patent Office are two completely different entities having separate expertise.

Experts say patent linkage undermines public health safeguards such as Bolar exception and compulsory licensing, which are key to the Indian Patent Act.

Bolar exception allows marketing approval of a generic when a patent is in place so that the generic can be introduced as soon as the patent expires.

A compulsory license, on the other hand, is issued if patented drugs are unavailable or unaffordable.

“Patent linkage could block marketing approval of generics, thereby rendering compulsory licenses useless and neutralise Bolar exception,”

Adams Vs Perrigo

Doctrine of Equivalence

Adams Vs Perrigo

U.S. Patent 6,372,252 Adams Therapeutics , Mucinex, Extended release formulation of guaifenesin,

In 2007,

Perrigo filed an Abbreviated New Drug Application for its own extended release guaifenesin product,

alleging in its paragraph (iv) certification (see 21 USC § 355(j)(2)(A)(vii)(IV)) that the claims of the ’252 patent are invalid or would not be infringed by the Perrigo product.

The doctrine of equivalents issue arises from claim 34, which recites (in relevant part) a “modified release

product” with “an AUC(inf) of at least 3500 hr*μg/mL.

Adams Vs Perrigo

Because the highest AUC value for Perrigo’s product was 3493.38 hr*μg/mL,

Adams sought to use the doctrine of equivalents to establish infringement.

However, the district court determined that the phrase “at least 3500” designated an absolute lower limit, such that resort to the doctrine of equivalents would impermissibly vitiate a claim limitation.

Adams Vs Perrigo

The Federal Circuit disagreed with the district court, noting the following: Previous Federal Circuit decisions permitted application of the doctrine of

equivalents to numeric ranges.

The “at least” language does not change the analysis—“at least” is just “the simplest way to express greater than or equal to.”

The lack of words of approximation (such as “about”) may affect the literal infringement analysis, but does not foreclose the doctrine of equivalents.

Adams Vs Perrigo

Providing guidance to the district court on remand, the Federal Circuit explained: ““The proper inquiry is whether the accused value is insubstantially different The proper inquiry is whether the accused value is insubstantially different

from the claimed value”.from the claimed value”.

Also interesting is the Federal Circuit’s footnote that “caution[s]” against reading the term “3500” with “greater precision” than it deserves.

The court makes reference to the concept of significant digits, noting that, “[i]n some scientific contexts, ‘1’ represents a less precise quantity than ‘1.0’”

Adams Vs Perrigo

It seems to me that interpreting and applying the claim language under a significant digits approach could bring the accused product within the literal scope of the claim. If the claimed value (3500) is interpreted as having only two 2 significant digits,

and

the accused value is reported with 2 significant digits for comparison, the 3493.38 accused value would be reported as 3500.

Since 3500=3500, the accused product would literally meet this claim limitation.

Adams Vs Perrigo

The modified release product of claim 26 [which claims the modified release product of claim 24 wherein the total quantity of guaifenesin is 600 mg] wherein the Cmax of said product is at least 1000 ng/mL and

said product has an AUCinf of at least 3500 hr*ng/mL.

Perrigo’s product has four mean AUC values, all of which are less than 3500 hr*ng/mL.

The highest value calculated was 3493.38 hr*ng/mL, which is within 0.189% of 3500 hr*ng/mL.

Adams Vs Perrigo

The district court stated that the term “at least” indicates an absolute lower limit of the range, citing

Quantum Corp. v. Rodime, It stated that allowing Adams to show infringement under the doctrine of

equivalents would vitiate the 3500 hr*ng/mL claim limitation.

On appeal, Adams argues that it should be allowed to establish infringement under the doctrine of equivalents.

Adams asserts that we previously concluded that infringement under the doctrine of equivalents could apply to claims requiring a specific numeric range.

Adams Vs Perrigo

It asserts that the question is whether Perrigo’s AUC value is insubstantially different from the claimed AUC value Adams contends that because 3494.38 hr*ng/mL is only 0.189% different from

3500 hr*ng/mL, a genuine issue of material fact exists with respect to whether the two values are insubstantially different.

Perrigo argues that because claim 34 does not use words of approximation, Adams cannot expand this element to

ensnare Perrigo’s ANDA product.

Perrigo asserts that “[t]his Court has expressly held that the claim term “‘at least’ means ‘as the minimum’ and there-fore when coupled with a specific number sets forth an absolute lower limit of a range

Adams Vs Perrigo

The addition of “at least” in this case does not change this analysis.

At least 3500 is the simplest way to express greater than or equal to 3500, an open-ended range.

We vacate the order of the district court

United States Court of Appeals for the Federal Circuit02-1348

GLAXO WELLCOME INC.,Plaintiff-Appellant,

v.ANDRX PHARMACEUTICALS, INC.,

Defendant-Appellee.

Glaxo Vs Andrx

Glaxo Wellcome, Inc. appeals the decision of the United States District Court for the Southern District of Florida, holding on summary judgment that United States Patent No. 5,427,798 (the '798 patent) is valid but not infringed by the bupropion products of Andrx Pharmaceuticals, Inc.[1]

We conclude that the district court erred in its construction of the '798 claims.

On the correct claim construction, we vacate the summary judgment of noninfringement and remand for further proceedings.

Glaxo Vs Andrx

BACKGROUND

Glaxo Products : antidepressant medicine having the brand name WellbutrinSR and the smoking-

cessation medicine having the brand name Zyban.

The active ingredient of both products is bupropion hydrochloride.

Glaxo manufactures and sells sustained release formulations of these products; sustained release extends the medicinal action of the bupropion so that less frequent doses

are required, and avoids the surge of bupropion that had occasionally caused seizures upon ingestion.

Sustained release formulations must maintain an effective level of the medicine in the bloodstream for an optimum period without unacceptable deviation in pharmacologic activity.

Glaxo Vs Andrx

Andrx filed two Abbreviated New Drug Applications (ANDA) seeking approval of

generic counterparts of the Glaxo sustained release products, asserting identity of active ingredient and properties with those of Wellbutrin7SR and Zyban7.

Andrx also filed a Paragraph IV certification, asserting that the Andrx products do not infringe the Glaxo '798 patent or that the patent is invalid:

Glaxo duly filed suit against Andrx for infringement of the '798 patent, in accordance with these statutory provisions

Glaxo Vs Andrx

The following claims of the '798 patent are representative:

1. A controlled sustained release tablet comprising 25 to 500 mg of bupropion hydrochloride and hydroxypropyl methylcellulose, the amount of hydroxypropyl methylcellulose to one part of bupropion

hydrochloride being 0.19 to 1.1

and said tablet having a surface to volume ratio of 3:1 to 25:1 cm-1

and said tablet having a shelf life of at least one year at 59" to 77"F. and 35 to 60% relative humidity,

said tablet releasing between about 20 and 60 percent of bupropion hydrochloride in water in 1 hour, between about 50 and 90 percent in 4 hours and not less than about 75 percent in 8 hours.

Glaxo Vs Andrx

The following claims of the '798 patent are representative: 14. A controlled sustained release tablet comprising an admixture of 100 mg

of bupropion hydrochloride and hydroxypropyl methylcellulose which after oral administration of a single one of said tablets in adult men produces plasma levels of bupropion as free base ranging between the minimum and maximum levels as shown in Fig. 5 over twenty-four hours.

18. A sustained release tablet containing a mixture of (a) 100 mg of bupropion hydrochloride and (b) means for releasing between about 25 and 45% of bupropion hydrochloride in one hour, between 60 and 85% in 4 hours and not less than 80% in eight hours in distilled water said means comprising hydroxypropyl methylcellulose.

Glaxo Vs Andrx

In determining the meaning and scope of patent claims, the court gives primary consideration to the specification and

the prosecution history, and

may consider the prior art and technical treatises and

dictionaries.

If relevant and helpful, the court may receive the testimony of experts in the field of the invention

Glaxo Vs Andrx

The issues of claim construction and infringement focused on the controlled release agent, hydroxypropyl methylcellulose (HPMC). HPMC is defined in the Handbook of Pharmaceutical Additives as follows: Definition: Propylene glycol ether of methyl cellulose

Properties: White powd.; swells in water to produce a clear to opalescent visc. colloidal sol'n.; nonionic, insol. in anhyd. alcohol, ether, chloroform; sol. in most polar solvs.

Trade Names: Benecel7 Hydroxypropyl Methylcellulose; Methocel7 E3 Premium; Methocel7 E4M Premium; Methocel7 E5P; Methocel7 E6 Premium; Methocel7 E10MP CR; Methocel7 E15LV Premium; Methocel7 E50LV Premium; Methocel7 E50P; Methocel7

E Premium; Methocel7 F4M Premium . . . .

Glaxo Vs Andrx

The specification describes the hydroxypropyl methylcellulose release agent as follows: This invention is directed to control sustained release (SR) tablets containing bupropion

hydrochloride (as the drug or active ingredient), preferably hydroxypropyl methylcellulose (Methocel7) for controlling drug release rate, and cysteine hydrochloride or glycine hydrochloride.

Methocel is the brand name for hydroxypropyl methylcellulose (HPMC) from Dow Chemical. Other companies also supply HPMC.

In order to prepare the controlled sustained release (SR) tablets of this invention, particles of bupropion hydrochloride are preferably blended with microcrystalline cellulose and hydroxypropyl methylcellulose (Methocel7) to form an admixture of blended powders.

In the practice of this invention, for every part by weight of bupropion hydrochloride, the amount of hydroxypropyl methylcellulose is 0.19 to 1.1 and more preferably 0.267 to 0.68 parts by weight . . . .

Glaxo Vs Andrx

'798 patent, col.1:67 - col.3:14. The specification describes the HPMC used in the examples as follows:

Hydroxypropyl Methylcellulose 2910, USP used in the examples, conforms to 28.0 to 30.00% methoxyl substitution and 7.0 to 12.0% hydroxypropyl substitution. The preferred nominal viscosity of 2% solution in water is not less than 3,000 centipoise and not more than 5,600 centipoise. It is supplied by Dow Chemical Company, Midland, Mich. as Methocel E4M Premium CR.

'798 patent, col.5:13-20. During prosecution of the '798 patent, the examiner required that all the claims be limited to

hydroxypropyl methylcellulose as the release agent. For example, claim 14, as originally submitted, was as follows:

14. A controlled sustained release tablet comprising an admixture of 100mg of bupropion hydrochloride and means for providing a shelf life of at least one year and after oral administration of a single one of said tablets in adult men producing plasma levels of bupropion as free base ranging substantially between the minimum and maximum levels as shown in Fig. 5 over twenty four hours.

Glaxo Vs Andrx

The examiner stated: The rate of release is directly related to the release retarding effect of

hydroxypropylmethylcellulose.

While other excipients have been disclosed, the particular cellulose is considered critical for controlled and/or sustained release and should be incorporated into the independent claims.

The disclosure of a single species does not provide a basis for claiming a generic concept.

Glaxo Vs Andrx

The applicant acquiesced, and limited all the claims to hydroxypropyl methylcellulose. However, the examiner did not require limiting the hydroxypropyl methylcellulose to any specific grade or molecular weight. What the examiner required was: Applicants are claiming a tablet which provides a distinct release profile.

The advantages provided by the unique tablet differ from an instant release tablet.

The limitations of claims 2-3 are considered critical and should be incorporated into claim 1 for proper enablement.

Glaxo Vs Andrx

In response, the applicant amended claim 1 to include the limitations: "said tablet releasing between about 20 and 60 percent of bupropion hydrochloride in water in 1 hour, between about 50 and 90 percent in 4 hours and not less than about 75 percent in 8 hours.“

Glaxo Vs Andrx

The examiner did not require "a particular grade" of HPMC.

The district court erred in holding that the amendment adding the release rate data to the claim limited the claim to the grade of HPMC in the example.

The district court stated: "All grades of HPMC could no longer be read into the Glaxo claims to a certainty after the amendment which recognized that a particular grade was critical for controlled or sustained release, therefore an invitation was extended to refer elsewhere for particular grade information."

Neither the applicant nor the examiner stated that "a particular grade was critical"; the amendment stated the parameters of the claimed release, not a particular grade of hydroxypropyl methylcellulose.

The HPMC was not limited to the specific example of grade 2910

Glaxo Vs Andrx

Andrx states that its HPMC has a significantly lower molecular weight and viscosity than

those of grade 2910, and that the Andrx HPMC does not affect the rate of release because it is readily soluble.

Andrx states that it controls the release of bupropion in other ways, not by way of the HPMC in its tablets.

Andrx states: "In the Andrx ANDA products, the Eudragit7E100/Ethocel 100 layer is the release controlling means.

This polymer mixture forms a polymeric membrane that regulates the amount of drug that is allowed to release from the pellets by diffusion through the membrane."

Andrx also states that its tablets do not exhibit the dissolution and blood plasma profiles required by the claims.

Glaxo Vs Andrx

Glaxo challenges these statements, pointing out that Andrx was unable to produce a satisfactory controlled release product without

using HPMC, and

that Andrx has represented to the FDA that its tablets are bioequivalent to the Glaxo tablets, as is required for an ANDA, and

thus necessarily match the release rate, dissolution, and blood plasma profiles of the federally approved formulation.

Glaxo Vs Andrx

Glaxo states that hydroxypropyl methylcellulose is a polymer and exists in a range of molecular weights, that it is incorrect to construe the claims as limited to a particular grade of hydroxypropyl methylcellulose, and that the specification contains no basis for either a molecular weight or a viscosity limitation.

Glaxo argues that while the specification shows the HPMC 2910 (supplied as Methocel E4M Premium CR) that Glaxo used, the description of the invention does not limit the HPMC to a particular grade

Glaxo Vs Andrx

Glaxo states that hydroxypropyl methylcellulose is a gel-forming material known for use in pharmaceutical formulations. There was extensive evidence to this effect. Professor Kathryn E. Uhrich (Rutgers University) testified as follows:

I : Significantly, all grades of HPMC are capable of forming a hydrogel that

contributes to sustained release when exposed to aqueous media, including the HPMC E5 grade of the Andrx ANDA products.

Andrx's products use HPMC E5 and clearly fall within the patented claim element for HPMC.

The accused products contain admixtures of HPMC E5 with bupropion and the resulting tablets are sustained release tablets where the HPMC E5 contributes to the release.

Glaxo Vs Andrx

II

The hydroxypropyl methylcellulose [in the Andrx products] is essential for the sustained or extended release of bupropion hydrochloride as a result of, among other things, the interactions of the hydroxypropyl methylcellulose with the adjacent bupropion/hydroxypropyl methylcellulose, as well as with the other polymers in the formulation during both manufacture and drug release.

The hydrophilic properties of hydroxypropyl methylcellulose and its ability to swell in the presence of solvents such as water and certain organic solvents are also important in controlling release.

Therefore, in Andrx's proposed 100 mg and 150 mg products, a means for releasing bupropion hydrochloride is hydroxypropyl methylcellulose as required by Claims 18 and 19.

Glaxo Vs Andrx

Dr. Banakar, Andrx's expert, described by Andrx as world renowned, testified that a person of ordinary skill in the art of drug formulation reading the '798 patent would understand that hydroxypropyl methylcellulose only includes certain grades of HPMC which are high-viscosity and hydrogel-forming. Dr. Banakar stated: If the term "hydroxypropyl methyl cellulose" as used in Claims 1, 14, 15, 18 and 19 of the '798

patent includes low-viscosity, low molecular weight grades of HPMC, then the '798 patent is not enabling of the claimed invention because it does not teach or enable one skilled in the art to make a sustained-release bupropion formulation having the dissolution profiles of Claims 1, 18 or 19 or the blood plasma drug levels of Claims 14 or 15.

That is, for a product to exhibit the dissolution profile recited in Claim 1 of the '798 patent, and only require the use of bupropion and HPMC, at the specified ratio, the HPMC must be of a high molecular weight, high-viscosity release-controlling grade. Use of a low-viscosity, low molecular weight soluble grade of HPMC such as the E5 grade at the recited ratios without some other sort of release-controlling technology added would make it impossible for one of ordinary skill in the art to obtain the required dissolution profile.

Glaxo Vs Andrx

In fact, in order to obtain a suitable sustained release formulation, which uses HPMC E5 as a binding agent and/or seal coat, constituent, Andrx needed to employ a completely different and novel release technology. . . .

The Andrx ANDA products do not employ hydrogel technology to control the release of bupropion. Instead, the Andrx ANDA products employ pellets (compressed into a tablet) having certain polymer coatings thereon, which control bupropion release by diffusion.

Glaxo Vs Andrx

Dr. Nicholas Peppas (Professor of Pharmacology, Purdue University) described by Glaxo as one of the world's leading scientific experts in hydrogels, disagreed with Dr. Banakar:

Each of Andrx's products comprises hydroxypropyl methylcellulose and bupropion hydrochloride and the hydroxypropyl methylcellulose is an essential component for the extended and sustained release of bupropion hydrochloride.

Its presence in Andrx's formulations and the interactions of the hydroxypropyl methylcellulose with other components inside of this formulation lead to the formation of a gel region in the polymer matrix, which, as I have shown in paragraphs 31, 32 and 36, is a controlling step of the overall release process.

Glaxo Vs Andrx

Dr. Nicholas Peppas (Professor of Pharmacology, Purdue University) described by Glaxo as one of the world's leading scientific experts in hydrogels, disagreed with Dr. Banakar: I disagree with Dr. Banakar's opinion [Andrx's expert] with respect to the characteristics of

hydroxypropyl methylcellulose and with Dr. Banakar's opinion that a person working in drug formulation or pharmaceutics would interpret Claims 1, 13, 14, 15, 17 and 19 of the '798 patent as limited only to hydroxypropyl methylcellulose grades that form "hydrogels" and would not include "low viscosity grades" of hydroxypropyl methylcellulose. In my opinion, and based on my experience, Dr. Banakar is incorrect in defining "low viscosity" grades of hydroxypropyl methylcellulose as not being "hydrogels."

For lower viscosity hydroxypropyl methylcellulose grades, these gels may be somewhat less dense than for higher viscosity hydroxypropyl methylcellulose grades, but the gels formed during swelling definitely control the drug release process in Andrx's products.

Glaxo Vs Andrx

Although the expert testimony is facially in conflict, it was not disputed that the mechanism whereby HPMC affects the release of materials with which it is mixed is the swelling of the HPMC in contact with water.

It was not disputed that Andrx mixes the bupropion with HPMC in the interior portion of its tablets.

Andrx did not establish that the HPMC it used to mix with the bupropion did not swell in water and affect the rate of release of the bupropion, while arguing that other chemicals affect diffusion. Glaxo stresses that in the Andrx formulation the HPMC is mixed with the bupropion at the core of the tablet, as in the '798 patent.

Glaxo Vs Andrx

Andrx in turn stresses that both Andrx and Glaxo use a rapidly soluble grade of HPMC as outer coatings of the tablet. The '798 patent describes the Glaxo outer coating as a thin film of HPMC that does not "substantially affect the release rate of the bupropion hydrochloride from the tablet, since the coating is instant release which rapidly dissolves in the stomach." The '798 specification explains that "because of the nature of the film coating, the release rate will be substantially the same whether or not the tablets are film-coated."

Andrx states that it uses this same grade inside its tablet in admixture with the bupropion, and therefore that it cannot contribute to controlling the rate of bupropion release.

Glaxo Vs Andrx

Glaxo responds with the testimony of Andrx's formulation scientist, Mr. Jianbo Xie, that he and others at Andrx had been unable to produce a sustained release bupropion product without using HPMC, although they had tried to do so because of the Glaxo patent.

By deposition Mr. Xie stated: Q: I'm asking what you were thinking when you were doing this development work in the

first half of 1997. Whatever the lawyers think or didn't think, weren't you trying to stay away from HPMC to avoid the patents?

A: If we could, we tried to -- how do you say that -- can you repeat your question again?

Q: You perceived your job so as to stay away from using HPMC if you could so that you could avoid infringement, that is what you were trying to do in early 1997; isn't that correct?

A: Yes, that was a part of the reason, part of the reason.

Glaxo Vs Andrx

As a matter of claim construction, the intrinsic and extrinsic evidence lead to the conclusion that the HPMC mixed with the bupropion at the core of the tablet is not limited to a particular grade and molecular weight, provided only that the claimed limitations of release rate and plasma levels are met.

When a claim term has an accepted scientific meaning, that meaning is generally not subject to restriction to the specific examples in the specification.

It is established that "as a general rule claims of a patent are not limited to the preferred embodiment . . . or to the examples listed within the patent specification.") ("preferred embodiments, without more, do not limit claim terms").

Glaxo Vs Andrx

In this case the properties and use of hydroxypropyl methylcellulose to control release were well known.

The examination record showed that patentability turned on the ratio of the HPMC to the bupropion, the shelf life, the rate of release, the duration of release, and the plasma levels.

The hydroxypropyl methylcellulose used in admixture with the bupropion hydrochloride is not limited to the grade and molecular weight of HPMC in the specific examples, but the claims, correctly construed, require that HPMC be present in the stated amount, and that the product have the release rate and duration and plasma levels and other properties set forth in the claims

Glaxo Vs Andrx

The factual issues arising under the doctrine of equivalents were similarly unresolved. In view of our ruling that literal infringement is not limited to a particular grade of HPMC, but that Glaxo must establish that all of the claim limitations are met by the Andrx product, the premise of district court's ruling on equivalency is no longer applicable. Further, that holding was based on the Federal Circuit's decision in Festo Corp.

v. Shoketsu Kinzoku Kogyo Kabushiki Co., 234 F.3d 558 (Fed. Cir. 2000) (en banc), which was vacated after the district court's decision. Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co., 535 U.S. 722 (2002). Thus the district court's decision on this ground is vacated.

Glaxo Vs Andrx

CONCLUSION

We conclude that the claims are not limited to a specific grade of hydroxypropyl methylcellulose as used in admixture with the bupropion. The summary judgment of noninfringement is vacated, and the case is remanded for further proceedings.

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Pharma IP Cases Part A