DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The claims are directed to a compound of formula I or a combination thereof. The limitation directed to “combination thereof” is indefinite. It is unclear if the combination thereof refers to the multiple compounds of formula I being separately present, in which case the claim is directed to “a composition”, not “a compound”; or if the combination refers to the combination of isomers, solvates, salts etc.
Claims 4 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 4 comprises a limitation directed to definition of R1 and also comprises preferred definition of R1. It’s unclear which R1 the claim is limited to or what limitation, if any, the term “preferably” imparts on the claim.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claims recite compound of formula I or solvates or polymorphs thereof. Solvates and polymorphs are crystal forms of the compound. Specification provides no evidence that any crystal forms of any of the compounds with the scope of Formula I have been prepared. Whether any given compound has a crystal form is highly unpredictable. Without detailed instruction of how to prepare a crystal form and identification of said form by Xray diffraction, DSC or other art accepted techniques, a skilled artisan would require extensive amount of experimentation in order to produce a crystal form, or multiple crystal forms in case of polymorphs. Since no crystal forms have been exemplified, Examiner concludes that applicants have not prepared crystal forms of compound I and were not in possession of solvates or polymorphs of compound I at the time of filing.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 9-12 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treatment of cancers mediated by KRAS G12C mutation, does not reasonably provide enablement for prevention of such cancers. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
A conclusion of lack of enablement means that, based on the evidence regarding each of the factors below, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation.
These factors include:
(A) The breadth of the claims;
(B) The nature of the invention;
(C )The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The breadth of the claims
Claims 8-12 are drawn to a method for preventing of cancers mediated by KRAS G12C mutation by administering the compound of claim 1 or the pharmaceutical composition of claim 8.
The state of the prior art
A search of prior art has failed to uncover preventive therapeutic agents for cancers mediated by KRAS G12C mutation. Applicants are invited to provide evidence to the contrary. In any event, the examiner notes that there is no art provided of record, evidence set forth in the disclosure, or correlation establishing some nexus to support preventive administration or therapy between the art and the instant disclosure to support the alleged cancer preventing applicability of compounds that bind and inhibit KRAS G12C activity. Art recognizes utility of KRAS G12C inhibitors, such as Sotorasib, in treatment of already diagnosed KRAS mutated cancers, but no prophylactic administration such inhibitors has been reported.
The level of one of ordinary skill
The skilled artisan in this field is that of an MD and/or a PhD skilled in the development and treatment of cancer.
The level of predictability in the art
The examiner acknowledges the probability and predictability that the instantly claimed salts have applicability in treating cancers mediated by KRAS G12C mutation. There is not seen sufficient data to substantiate the assertion that cancer may be prevented by the compounds of the instant invention. One skilled in this art would not predict from the disclosure provided that cancer can be prevented in view of the data and examples provided.
The amount of direction provided by the inventor and working examples.
The instant specification is not seen to provide adequate guidance, which would allow the skilled artisan to extrapolate from the same to establish enablement for the prevention of cancer. Specification provides antiproliferation assay data using NCI-H358 cells which overexpress KRAS G12C (Example 1). Specification also provides data indicating selectivity of the claimed active agent towards cell lines that overexpress KRAS G12C (Example 5). However, there is no data that would indicate that administration of compound of formula I prevents the cancer-causing mutation in KRAS G12C. It appears the claimed agents act on cancer cells to reduce their proliferation, which requires the subject to already have cancerous cells.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Indeed, in view of the information set forth supra, the instant disclosure is not seen to be sufficient to enable the prevention of cancer and the skilled artisan would not extrapolate preventive efficacy from the compounds instantly claimed. Whether any of the compounds within the scope of pending claims can prophylactically be administered to subjects who are at risk of developing KRAS G12C mutation is highly unpredictable and based on the examples and proposed mechanism of action is highly unlikely.
Claims 1-6 and 8-12 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for using the compounds of claim 1 with Ring A as a piperazine ring, R2 as a pyrrolidine (as monocycle or as a part of a bicyclic structure ring), does not reasonably provide enablement for using compounds of the full scope of the rejected claims. The specification is not adequately enabled for the scope of fused rings that have diverse groups as Ring A or as Group R2. Compounds made and tested represent the scope of claim 7, not claim 1. The specification does not enable any skilled pharmacologist or physician to use the invention commensurate in scope with these claims. The factors to be considered in making an enablement rejection have been summarized above.
a) Determining if any particular claimed compounds with various rings as A and the numerous possible substituents as R2 would be active would require synthesis of the substrate and subjecting it to testing with Applicants' NCI-H358 cell antiproliferation assay (see test example 1). Considering the large number of compounds to be made this is a large quantity of experimentation.
b) The direction concerning the claimed compounds is found in line Summary portion of the specification, pages 2-7, which merely states Applicants' intent to make and use such compounds.
c) In the instant case none of the working examples contains any compounds where Ring A is anything other than piperazine and R2 is anything other than a pyrrolidine containing group.
d) The nature of the invention is inhibition of cancer cell proliferation and treatment of human diseases with Applicants' compounds. This involves physiological activity. The nature of the invention requires an understanding of the mechanism of action, specifically the ability of those compounds to inhibit KRAS enzyme in cells with KRAS mutation. In view of the unpredictability of receptor binding activity and claimed divergent substituents with varied polarity, size, and polarisability, the skilled physician would indeed question the inclusion of such diverse rings, commensurate in scope with these claims. Also see the MPEP § 2164.03 for enablement requirements in the structure sensitive arts of pharmacology and medicinal chemistry.
e) The state of the art is detailed knowledge of the claimed compound’s binding to the KRAS receptor is lacking. No X-ray structure of the receptor is known and the structural requirements of ligands to this receptor are poorly understood. Even within the exemplified compounds with what Examiner has indicated as enabled substitutions, there is significant different in efficacy. IC50 of the tested compounds varies by orders of magnitude which indicates great sensitivity with regards to substituents.
Compounds made and tested represent the scope of claim 7 not claim 1.
f) The artisan using Applicants' invention to treat diseases with the claimed compounds would be a physician with a MD degree and several years of experience. He would be unaware of how to predict a priori how a changing a heterocyclic ring would affect biological activity. In view of the divergent rings with varied basicity, steric hindrance, and polarisability, the skilled physician would indeed question the inclusion of such fused rings, commensurate in scope with these claims. g) Physiological activity, is well-known to be unpredictable, In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). h) The breadth of the claims includes all of millions of compounds of formula (I). Thus, the scope is very broad. The present claims embrace various heterocyclic radicals, which are not art-recognized as equivalent. The specific compounds made are not adequately representative of the compounds embraced by the extensive Markush groups instantly claimed.
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here. Thus, undue experimentation will be required to practice Applicants' invention.
Conclusion
Claims 1-12 are pending
Claims 1-12 are rejected
Any inquiry concerning this communication or earlier communications from the examiner should be directed to YEVGENY VALENROD whose telephone number is (571)272-9049. The examiner can normally be reached Mon-Fri 9am-5pm.
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/YEVGENY VALENROD/Primary Examiner, Art Unit 1628