Patent validation and Inherent Unobviousness

A patent is a territorial right granted by the government of the territory to an inventor to exclude others from making, using, offering for sale, or selling an invention throughout the territory or importing the invention into the territory for a limited time. Foremost criteria for the grant of a patent application for an invention is that the invention should be new, i.e. 1) The invention must be novel, e.g., not disclosed in any of the prior art reference and 2) The invention must be non-obvious, e.g., the invention should not be obvious to any person who is skilled in the art on the date of filing of the invention as patent application. Another criterion for the grant of the patent is industrial use of the invention.

If a granted patent is blocking any product ready to be commercialized, then it is the strategy of the company whose product is ready to be commercialized to invalidate the patent. Invalidation of the granted patent is prosecuted in judicial courts. According to certain patent office rules, patent invalidation cases can be initiated by "Any person interested". "Any person interested" can be defined as a person engaged in, or in promoting research in the same field as to which the invention relates. Patent can be invalidated on various grounds.

Grounds / strategies for the invalidation of a patent which are followed by attorneys in the judicial courts are:

• Invention claimed in the patent is not novel. The claimed invention is present in the prior art as any published document. If the claimed invention is lacking novelty with regards to the earlier disclosed knowledge or prior use can invalidate the patent.
• Subject of the claim of the patent is not an invention.
  

  Patent offices of each jurisdiction have a patent law suiting to the respective jurisdiction, which defines the patentable subject matter. An invention not falling in the criteria of the patentable subject matter can be invalidated on the grounds that the subject of the claim of the patent is not an invention according to the patent law of that country.

• Patent was wrongfully obtained by a person other than the person entitled.
  

  Applicants of the patent should be the inventors who have worked on the invention. Insufficient disclosure of inventors' details or disclosure of a person as an inventor who is wrongfully mentioned to be the inventor can form the basis of invalidation of patent. The issue here is that a patent may be invalidated or revoked in many jurisdictions, if the patent applicant or inventor is not the true and first inventor.

• Insufficient disclosure of the invention: It is the duty of the inventors to disclose all material information relating to the invention, including the best mode to accomplish the invention, all material art known to the inventor, and any information that might render the invention unpatentable, such as a public use or published description of the invention occurring more than one year prior to the filing date of the patent application. Any deliberate efforts for insufficient disclosure or description of information related to the invention can form the basis for invalidation of the patent. Another basis for invalidation of patent is false suggestion or representation to any fact or statement made in connection to the grant of the patent.
• Obviousness
  

  Claimed invention is obvious to any person skilled in the art and does not involve any inventive step can be invalidated on the basis of obviousness. If a person skilled in the art (appointed by the court) considers the claimed invention to be evident and easily discoverable as of on the priority date of the claimed invention, then the claim of the patent can be invalidated on the grounds of obviousness. US Supreme court judgment in 2007 in Teleflex Vs KSR case has broadened the scope of obviousness. Supreme Court invalidated the Teleflex patent stating that the information from different prior art references or products can be combined to ascertain if a person skilled in the art can get teaching, stimulation and motivation (TSM test) to obtain the subject matter invention. Instead of TSM it can be referred to ATM (Anticipation, Teaching, Motivation) for knowledge bank like bank ATM for financial matters.

• The claims included in the patent are not fully substantiated by the description provided.
• Failure to disclose information relating to foreign applications.
• First to file / First to invent US patent laws had been following the patentability criteria to be ‘first to invent’ where as other countries patent laws followed the ‘First to file’ concept. In US, earlier invalidation of the patent could be based on first to invent basis where any inventor who has first invented the invention is given preference. However, to ensure patent law uniformity, US patent law has been amended and the patentability criterion is now based on first to file.
• Patent holder did not exercise diligence in pursuing the patent application process (Patent grace period)

In pharma sector, Hatch Waxman rule provides a balance to both inventors and generic players. FDA (Food and Drug Administration) cannot accept any ANDA (WHAT DOES THIS STAND FOR?) from the generic player for 5 years from the NDA approval date owing to data exclusivity. Similarly, generic player does not have to wait for the product patent expiry and instead can file ANDA under paragraph IV if there is an opportunity for the invalidation of the product patent. Generally the patent invalidation is based on obviousness under 35USC 103 in US and Art. 56 in EPC. Mostly the generic players challenge the validity of the product patent based on obviousness from the similar prior art molecule which can be considered as Markus molecule of the product patent and applying KSR-Teleflex supreme court judgment. Generic player asserts that the subject matter invention is based on the prior art molecule as a lead molecule with same indicative biological activity but novel due to different substituent pattern which passes ATM test (Anticipation, teaching and Motivation) as a person skilled in the art can arrive at the subject matter invention by anticipating and getting teaching and motivation by combining technical expertise and skill with knowledge from a whole lot of prior art information.

Generic player can challenge the product patent stating that similar base/lead molecule disclosed in the prior art makes the subject matter novel molecule obvious and the same biological activity disclosed for the similar base molecule validates the fact that the desired biological activity in the drug molecule is inherently obvious from the prior art and the drug molecule is the result of standard optimization process, therefore, not patentable. It is a real challenge for the inventor to defend the patent by justifying that the subject matter invention both in respect of novelty and inventive features fails the TSM (ATM) test and the invention is both in respect of chemical nature and biological activity unobvious to the prior art as a person skilled in the art can neither anticipate nor gets teaching or motivation to think of the novel target molecule and nor passes ATM test for the optimum biological activity of the target novel molecule. When changes made to the set of molecules disclosed in the prior art are technically explainable and justifiable by due diligence of all the available prior art information and knowledge and a person skilled in the art applying expertise in a logical manner can think of and arrive at the target commercialisable novel molecule by applying standard optimization approach and the same pharmaceutical activity with some shortcomings is already disclosed for the similar class of molecules then by applying KSR concept it can be considered that the target novel molecule is obvious and the pharmaceutical activity inherently exists in the similar class of molecules, therefore, the subject matter invention is inherently obvious, therefore, invalid.

Inherency is a puzzle that runs throughout patent law. Inherency is also perhaps the most elusive doctrine in all of patent law. The cases appear to flatly contradict each other, are often accompanied byDissents. Patents are based upon descriptions of technology. The description of the invention in a patent distinguishes it from previous technologies described in the prior art. The description of the claimed invention in a patent determines whether an accused device/product/process infringes the patent. The description of the invention in a patent application is used to determine whether the claimed invention is sufficiently novel, useful, and non obvious to merit a patent at all. Indeed, the fundamental premise of patent law is that of a bargain between the inventor and the public: the public authorizes twenty years of exclusive rights in exchange for the publication of inventive technology.

Technologies may have qualities/characteristics that are unappreciated or unidentified in a patent description, but which are nonetheless present. The law refers to these unknown attributes as "inherent" in the product or process. What should be done about such characteristics or qualities of a technology that exist but are not explicitly described, either through ignorance or inadvertence? This problem is explicitly presented in at least five different patent doctrines: anticipation, the on-sale bar, priority disputes, double-patenting, and enablement , and it casts its shadow across the law governing subject matter, infringement, and obviousness. The Federal Circuit has decided dozens of cases involving inherency in past. Depending on how it has been applied, the inherency doctrine permits defendants to invalidate a patent by showing that even though the prior art did not expressly disclose what the patentee claims to have invented, all or part of the patentee's invention was inherent in a particular piece of prior art.

However, as regards drug molecule, if the changes made in the base molecule disclosed in the prior art are contrary to the teachings based on due diligence of the information/knowledge available in the prior art and the changes made results into a novel molecule which based on clinical trials is a commercialiseable drug then KSR case is not applicable as the changes made are non obvious and the optimum pharmaceutical activity achieved in the target molecule is also non obvious. In this case, it can be stated that the invention in respect of chemical nature and optimum pharmaceutical properties is inherently non obvious, therefore, valid. Such cases are prima facie contrary to KSR-Teleflex obviousness as structurally, the target molecule is based on known base molecule having the said pharmaceutical activity but the novel aspect of the molecule with improved commercialiseable pharmaceutical activity is non obvious as the changes made to the molecules are not ascertainable from the disclosed/documented prior art by a person skilled in the art. Even though the same pharmaceutical activity is expressed by a set of similar base molecules and owing to toxic and insufficient biological activity, none of them can be commercialized. However, an inventor against the teachings from the prior art, optimizes the molecule which passes the regulatory tests and gets commercialized. The chemical structural changes made during optimization process in the light of changes in the pharmaceutical activity associated with the analogues are contrary to the teaching, and a person skilled in the art will not undertake such optimization as such changes as disclosed in the prior art reduce the pharmaceutical activity. In such a case, KSR-Teleflex concept is not applicable despite the fact that the target novel molecule is an analogue of known molecule having similar biological activity. Such inventions can be designated as inherently non obvious.

Inherency by definition concerns things that people of ordinary skill in the art do not know; if the person having ordinary skill in the art (PHOSITA) would know of the presence of an element based on the prior art disclosure, there is a straightforward case of anticipation based on that disclosure and no need for the Inherency doctrine.' Rather, the inherency cases are all ultimately about whether the public already gets the benefit of the claimed element or invention. If the public already benefits from the invention, even if they don't know why, the invention is inherent in the prior art. If the public doesn't benefit from the invention, there is no inherency.

In this article we examine main thread of inherent non obvious case.

Aripiprazole is the active ingredient in the anti-psychotic drug marketed by Otsuka Pharmaceutical Co., Ltd. (“Otsuka”) under the brand name Abilify®. It was approved in 2002 by the FDA and is marketed for the treatment of schizophrenia, bipolar disorder, irritability associated with autistic disorder in pediatric patients, and as an add-on treatment for depression. Abilify® has been commercially successful; the world sales have exceeded billion US$ and in 2010 were $4.5 billion.

Aripiprazole has the chemical name 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydrocarbostyril and has the following chemical structure:

Aripiprazole molecule is protected by U.S. Patent 5,006,528 which expires on April 20, 2015. Generic players Sandoz, Apotex and Teva had submitted Abbreviated New Drug Application (“ANDA”) filings under paragraph IV for the product patent to the FDA for approval to engage in the commercial manufacture, use, or sale of generic aripiprazole products. Otsuka brought actions against these generic drug manufacturers for patent infringement. The Defendants conceded that their ANDA filings constituted literal infringement but asserted in defense and counterclaimed that the claims were invalid for obviousness and obviousness-type double patenting. The district court held a bench trial and entered its Amended Memorandum Opinion. On the issue of obviousness under § 103, the court concluded that the Defendants failed to prove by clear and convincing evidence that the asserted claims would have been obvious to one of ordinary skill. In its analysis, the court considered the known carbostyril derivatives, with particular emphasis on the three purported “lead compounds” asserted by the Defendants.

The first of the Defendants’ alleged lead compounds is 7-[4-(4-phenylpiperazinyl)-butoxy]-3,4-dihydrocarbostyril, which has the following chemical structure:

"unsubstituted butoxy linker"

The only difference is that Aripiprazole has Cl substituent’s at positions 2 and 3 of phenyl ring. The unsubstituted carbostyril moiety (WHAT DOES THIS MEAN) with butoxy linkage is disclosed and claimed in Otsuka’s earlier U.S. Patent 4,734,416 (the “’416 patent”), which the parties agree is prior art to the ’528 patent. Entitled “Pharmaceutically Useful Carbostyril Derivatives,” the ’416 patent teaches a broad genus encompassing a very large No. of compounds. The ’416 patent discloses that “carbostyril derivatives having antihistaminic action and central nervous controlling action are useful as antihistaminic agents or central nervous controlling agents.

During the prosecution of ‘416 patent application, the co-inventor had submitted a declaration comparing 3 sets of biological test data comparing certain carbostyril derivatives. The declaration provides test data for antipsychotic activity for 9 carbostyril compounds comparing with 2 prior art reference compounds. The potency of compounds is indicated with an effective dosage (ED50), measured in milligrams per kilogram, wherein lower value indicates greater potency. The test results are summarized in Table-1 given below:

Compound No.	Chemical Name		ED50
5	5-[3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril dihydrochlo-ride		2.1
6	7-[3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril dihydrochlo-ride		9.3
16	7-{3-[4-(4-chlorophenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril		15.1
39	7-{3-[4-(3-chlorophenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril		2.5
41	7-[4-(4-phenyl-1-piperazinyl)butoxy]-3,4-dihydrocarbostyril (“unsubsti-tuted butoxy”)		5.5
42	1-methyl-7-[3-(4-phenyl-1-piperazinyl)propoxy]-3,4-dihydrocarbostyril		10.7
43	7-{3-[4-(2-chlorophenyl)-1-piperazinyl]propoxy}-3,4-dihydrocarbostyril		3.4
44	5-{3-[4-(2-ethoxyphenyl)-1-piperazinyl]propoxy}-3,4-dihydrocarbostyril		0.53
45	5-{3-[4-(4-methylphenyl)-1-piperazinyl]propoxy}-3,4-dihydrocarbostyril		8.1

Compound No. 44 having ED50 of 0.53 is most active. It has propyloxy linker attached to position 5 of carbostyril moiety and ethoxy substituent at position 2 of the phenyl moiety. Higher ED50 (2.1) of compound No. 5 indicates that biological activity reduces when ethoxy substituent is removed from the compound No. 44.

Compound No.41 has ED50 value of 5.5 and is unsubstituted analogue having butoxy linker at position 7 of carbostyril moiety. It corresponds to compound No. 5 which is unsubstituted analogue having propyloxy linker at position 5 of carbostyril moiety having ED50 value 2.1. However,compound Nos.6 and 41 are unsubstituted analogues differing in the size of linker attached at position 7 of the carbostyril moiety. Compound No.41 has ED50 5.5 compared to 9.3 for compound No.6. This indicates that compound with butoxy linker at position 7has better biological activity than the corresponding compound having propyloxy linkage at same position. But changing the position of propylxy linker to position 5 in compound No 6 results in compound No. 5 having four times more activity than corresponding compound with same linker at position 7 and 2 times more than corresponding compound having butyloxy linker at position 7. Considering optimization of a base molecule with propyloxy linker at position 7 by introducing chloro gp in the phenyl ring, the biological activity data indicates that Cl gp at position 2 (Compd. No.43)increases the activity from ED50 9.3 to 3.4 and Cl Gp at position 4 (Compd. No.6) reduces the biological activity as E D50 value increases from 3.4 to 15.1.

Foregoings in a vivid manner indicate that compound No. 41 which is an unsubstituted analogue of Aripiprazole can’t be a lead molecule for Aripiprazole because a person skilled in the art ascertains that propyloxy linker at position 5 of carbostyril moiety when replaced with butyloxy linker at position 7 reduces the biological activity of the molecule. An artisan can not anticipate from the prior art that compound of formula 41 can be taken as a lead molecule for the development of Aripiprazole as the change of linker position and replacement of ethoxy group with chloro group in phenyl ring results in drastic decrease in biological activity.

It is obvious that Aripiprazole molecule is inherently non obvious as the corresponding unsubstituted is not a lead molecule as an artisan can’t ascertain or anticipate success based on due diligence of prior art information, therefore, the patent ‘528 is valid.

Dr. C.K. Sehgal

Head-IPR

Arch Pharmalabs Ltd