DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-2 are pending.
Priority
This application is filed 12/14/2023 and claims the benefit of domestic priority as below:
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Information Disclosure Statements
Two IDS(s) received 12/14/2023, and all references from IDS(s) have been considered unless marked with a strikethrough.
Claim Objections
Claim 2 is objected to because of the following informalities:
The compound name contains a nomenclature error, in which the same position number is incorrectly assigned to a different substituent.
N-(4-((3-fluoro-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide,
N-(4-((3-methyl-2-methoxy-3-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide
Appropriate correction is required.
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 1-2 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. Because the specification, while being enabling for enhancing penetration of Formula (I) into the brain by administering the compounds of Formula (I), does not reasonably provide enablement for treating any neurodegenerative disease comprising administering Formula (I). However, specification does not reasonably provide enable the full scope of the claimed method of treating neurodegenerative diseases without undue experimentation. The disclosure does not enable any person skilled in the art to practice the invention commensurate in scope with the breadth of the claims.
The instant claims are drawn to a method of treating a disease, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound according to claim 1, wherein the disease is a neurodegenerative disease. The instant specification fails to provide information that would allow the skilled artisan to practice the treatment of every single neurodegenerative disease in existence.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
1.The nature of the invention, state and predictability of the art, and relative skill level
The invention recites a method of treating a disease, comprising administering to a patient in need of such treatment a therapeutically-effective amount of a compound according to claim 1, wherein the disease is a neurodegenerative disease selected from Alzheimer's disease, Parkinson's disease, ALS or Multiple Sclerosis. The relative skill of those in the art is high, that of an MD or Ph.D.
That factor is outweighed, however, by the unpredictable nature of the art. As illustrative of the state of the art, the examiner cites the fact that while applicant demonstrated that the compounds of Formula (I) of the instant invention are effective in penetrating or crossing the brain barrier as compared to similar compounds, nowhere in the specification did applicant demonstrate actual treatment of any neurodegenerative disease. For example, Alzheimer’s disease is characterized by amyloid-beta and tau proteins accumulation that lead to plaques in the brain and yet nowhere in the specification did Applicant demonstrate actual reduction of plaques or protein deposition in the brain. On the contrary, Parkinson disease is characterized by frontal cortex atrophy and ventricular enlargement and loss of pigmentation in the locus coeruleus and again the specification failed to demonstrate enhancement of pigmentation in the locus coeruleus or attenuation of the loss of said pigmentation when Formula (I) are administered.
The Examiner acknowledges that such teaching provide a mechanistic link between TYK-2 signaling and Alzheimer’s disease from a prior art. However, even assuming that TYK-2 inhibition may provide some degree of predictability with respect to Alzheimer’s disease, all of treatment of claimed neurodegenerative disease including Parkinson disease will not be explained. The specification does not provide comparable mechanistic support or therapeutic efficacy data for other distinct neurodegenerative diseases encompassed by the claims.
What applicant did demonstrate in table 2 is higher brain to plasma ratio of Formula (I) in the brain (instant specification page 59). Moreover, the examiner contends that neurodegenerative diseases are contrastingly different and therefore any inference made for one type of neurodegenerative disease cannot be assigned to other neurodegenerative diseases as their mechanism and/or etiology are contrastingly different. Given that applicant has yet to provide any data demonstrating treatment of an actual neurodegenerative disease, the Examiner maintains that Applicant has yet to enable the full breadth of the claims.
2. The breadth of the claims
The claims recite treatment of “a neurodegenerative disease selected from Alzheimer's disease, Parkinson's disease, ALS or Multiple Sclerosis”. This encompasses a wide range of mechanistic pathways of the diseases. Even if TYK-2 inhibition may be reasonably predictive for Alzheimer’s disease based on mechanistic discussion, the claims extend well beyond that single disorder. As a practical matter, it is nearly impossible to conclude that enhanced penetration of Formula (I) into the brain actually lead to any treatment, let alone to treatment of every single neurodegenerative disease of claims by administering the same compound.
3. The amount of direction or guidance provided and the presence or absence of working examples
The specification only provides enhanced penetration to the brain with Formula (I) (instant specification table 2, page 58-59). No direction or guidance for the treatment of any neurodegenerative disease, and working example demonstrating actual therapeutic efficacy in any neurodegenerative disease model are provided. Moreover, no reasonably specific guidance is provided concerning useful therapeutic protocols for treating neurodegenerative disease with Formula (I), other than enhanced penetration to the brain with Formula (I).
The instant disclosure provides no evidence to suggest that this unique activity can be extrapolated to progressive supranuclear palsy (PSP), for example, having unrelated mechanisms of action to multiple sclerosis, Alzheimer, and Parkinson and characterized by alpha-synuclein and tau pathology and neuronal loss in various parts of the brain, and thus does not meet the “how to use” prong of 35 USC 112, first paragraph with regard thereto.
4. The quantity of experimentation necessary
In view of the breadth of the claims and the absence of disease specific efficacy data, a person of ordinary skill in the art would be required to undertake substantial research to determine whether the claimed compounds are effective for treating each neurodegenerative disease encompassed by the claims. Instant application would include disease specific mechanistic validation, in vitro/in vivo models and dose optimizations. Such experimentation would not be routine and would constitute undue experimentation.
Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2 are rejected under 35 U.S.C. 103 as being unpatentable over Bohan (WO 2020/086616 A1, pub’d 04/30/2020, cited in IDS) in view of Moslin et al. (WO 2014/074660 A1, pub’d 05/15/2014).
With respect to independent claim 1, the claim recite that a method of treating a neurodegenerative disease selected from Alzheimer's disease, Parkinson's disease, ALS or Multiple Sclerosis by administering to the patient a therapeutically effective amount of a compound of Formula (I), or variant thereof.
Bohan teaches that the compounds and methods of using for inhibiting nonreceptor tyrosine protein kinase 2 (TYK-2), and these inhibitors treats TYK-2-mediated disorders includes neurological diseases such as Alzheimer’s disease (paragraph [0002], [00405], and claims 39-44). Bohan further teaches that structural modification of heteroaryl moieties and substituents is desirable to improve properties relevant to treatment of TYK-2-mediated disorders, including potency and drug-like characteristics (claims 39, and 40).
Bohan fails to teach a compound having a 1,2,3-triazole heteroaryl moiety as recited in the instant claims, and instead discloses TYK-2 inhibitors comprising a 1,2,4-triazole heteroaryl ring system. Bohan discloses a five membered heteroaryl ring system comprising a 1,2,4-triazole, whereas the instant application recites a 1,2,3-triazole (claim 39).
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(instant claim 1) (compounds from Bohan)
Moslin disclosures that TYK-2 inhibitory compounds, and teaches that multiple five membered nitrogen containing heterocycles, including pyrazolyl, imidazolyl, triazolyl, and tetrazolyl groups, are interchangeable heteroaryl design options within the same TYK-2 inhibitor framework (claims 2, 12, and scheme 8). Moslin further teaches that groups and substituents may be chosen by one skilled in the field to provide stable moieties and compounds and compounds useful as pharmaceutically-acceptable compounds and/or intermediate compounds useful in making pharmaceutically-acceptable compounds (paragraph [0095]). Instant application also demonstrate the comparison between instant claimed compounds and Bohan’s compounds in table 2 is higher brain to plasma ratio of Formula (I) in the brain (see specs., table 2, pg. 58-59).
It would have been obvious to a PHOSITA at the time of the invention to substitute a 1,2,4-triazole heteroaryl ring of Bohan to other multiple amine-contained heteroaryl ring as taught by Moslin. In the field of medicinal chemistry, structurally similar compounds are expected to have similar properties, particularly where the compounds are directed to inhibition of the same enzyme. (see MPEP 2144.09). Both Bohan and Moslin disclose TYK-2 inhibitors, and the heteroaryl rings at issue are closely related nitrogen containing heterocycles. Therefore, one of ordinary skill in the art would have reasonably expected that substituting one triazole ring for another structurally similar heteroaryl ring would maintain TYK-2 inhibitory activity while potentially improving drug like properties. For example, Bohan teaches TYK-2 inhibitor compounds having activity against neurological disorders such as Alzheimer’s disease, incorporating alternative heteroaryl groups taught by Moslin provide predictable medicinal chemistry advantages. Given the close structural similarity of the heteroaryl rings and their common function within TYK-2 inhibitory framework, such substitution represents a predictable variation.
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Applying KSR example rationale (B) in claim 1, it would have been prima facie obvious to substitute one ring of a TYK-2 inhibitor compounds having activity against neurological disorders taught by Bohan incorporating the triazole heteroaryl option taught by Moslin. The substitution merely substitutes one known, structurally similar heteroaryl ring for another in the same enzymatic context, yielding predictable results in view of the expectation that compounds similar in structure will have similar properties. (see MPEP 2144.09; In re Payne; In re Dillon)
With respect to claim 2, the claim recite that a method of treating a disease by administering a therapeutically effective amount of specific compounds, each comprising a heteroaryl amine linked to a cyclopropane carboxamide moiety, wherein the heteroaryl portion includes a 1,2,3-triazole.
As discussed above, Bohan teaches that the inhibitors as nonreceptor tyrosine-protein kinase 2 (TYK-2) for treating TYK-2-mediated disorders includes Alzheimer’s disease (paragraph [0002], [00405], and claims 39-44), and structural modification of heteroaryl moieties and substituents is desirable to improve their property for treating TYK-2-mediated disorders (claims 39, and 40). Moslin teaches that heteroaryl groups are interchangeable within the TYK-2 inhibitor framework and that such substitution provide predictable improvements in drug-like properties (claim 2, and scheme 8).
Although, Bohan and Moslin do not explicitly disclose that specific compounds recited in claim 2, the TYK-2 inhibitor structure, N-(4-((3-methoxy-4-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide in instant claim 2 differ from the TYK-2 inhibitor structure disclosed in Bohan (claim 39) by substitution of 1,2,4-triazol with 1,2,3-triazol, a modification taught by Moslin (e.g.,N-(4-((3-methoxy-4-(2-methyl-2H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide) as an interchangeable design option providing improved drug-like properties while retaining TYK-2 inhibitory activity.
In view of the close structural similarly of the disclosed heteroaryl rings and their shared role in TYK-2 inhibition, one of ordinary skill in the art would have reasonably expected that incorporation of the 1,2,3-triazole heteroaryl group would maintain TYK-2 inhibitory activity and therapeutic utility.
Applying KSR example rationale (A), it would have been prima facie obvious to arrive at the compounds of claim 2 by combining the teaching of Bohan and Moslin. The combination merely substitutes one known, structurally similar heteroaryl ring for another in the same enzymatic context, yielding predictable results in view of the expectation that compounds similar in structure will have similar properties. (see MPEP 2141, and 2144.09)
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
The instant application is not filed as a result of a restriction requirement, and therefore the safe harbor provision of 35 USC § 121 does not apply. (see MPEP 804.01)
Claims 1-2 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, and 4 of U.S. Patent No. US11,884,650 B2 (Spergel et al.). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of Spergel have the same compounds as presently recited in the claim 1, and the disclosure provides the instant treatment utility.
The claims of Spergel fail to teach the utility of treating a disease, comprising administering to a patient for a neurodegenerative disease selected from Alzheimer's disease, Parkinson's disease, ALS or Multiple Sclerosis.
However, it would be prima facie obvious to one having ordinary skill in the art to arrive at the utility because it is proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. (see MPEP 804)
In this case looking to the disclosure provides the instant treatment utility, and claims 1, and 2 are not patentably distinct from the claims of Spergel.
Conclusion
Claims 1-2 are rejected.
Claim 2 is objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEONG JONG KIM whose telephone number is (571)272-6918. The examiner can normally be reached 7:00am-3:30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton A. Brooks can be reached at 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SEONG JONG KIM/ Examiner, Art Unit 1621
/CLINTON A BROOKS/ Supervisory Patent Examiner, Art Unit 1621