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 .
Status of claims
Claims 1-4, 7, 10, 12, 14, 1721-22, 24-25, 29, 31-34, and 38 are currently pending and under consideration.
Claim Rejections - 35 USC § 112 (Enablement)
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 33-34 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 claims contain 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 use the invention.
The specification does not reasonably provide enablement for treating a condition,
disease, or disorder is selected from cachexia; anorexia or anorexia nervosa; nausea; emesis;
weight loss; failure to thrive; sarcopenia; muscle wasting; muscle weakness; frailty; osteoporosis; bone disorders; pain; neuropathic pain; anxiety; depression; hypertension; malnutrition; obesity; sexual dysfunction; and inflammatory disease.
The specification does not enable any person skilled in the art (POSITA) to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The how to use requirement of the enablement statute, when applied to method claim, refers to operability and how to make the claimed method work "The factors to be considered (in making an enablement rejection) have been summarized as the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims", In re Rainer 146 USPQ 218 (1965); In re Colianni, 195 USPQ 150, Ex parte Formal, 230USPQ 546. The issue is the correlation between clinical efficacy for treating cachexia; anorexia or anorexia nervosa; nausea; emesis; weight loss; failure to thrive; sarcopenia; muscle wasting; muscle weakness; frailty; osteoporosis; bone disorders; pain; neuropathic pain; anxiety; depression; hypertension; malnutrition; obesity; sexual dysfunction; and inflammatory disease and Applicants' in vitro affinity assay using hMC4R and MC4R Antagonist Potency Assay.
a) Determining if any compound embraced by the claims would treat cachexia; anorexia or anorexia nervosa; nausea; emesis; weight loss; failure to thrive; sarcopenia; muscle wasting; muscle weakness; frailty; osteoporosis; bone disorders; pain; neuropathic pain; anxiety; depression; hypertension; malnutrition; obesity; sexual dysfunction; and inflammatory disease would require synthesis of the compound, formulation into a suitable dosage form, and subjecting it to clinical trials with a number of fundamentally different diseases listed above, or to testing them in an assay known to be correlated to clinical efficacy of such treatment. This would require a large degree of unduly burdensome experimentation.
b) The direction concerning treating these diseases found in the specification merely
states Applicants' intention to do so. Since no MCAR antagonist has ever been used to treat
cachexia; anorexia or anorexia nervosa; nausea; emesis; weight loss; failure to thrive; sarcopenia; muscle wasting; muscle weakness; frailty; osteoporosis; bone disorders; pain; neuropathic pain;
anxiety; depression; hypertension; malnutrition; obesity; sexual dysfunction; and inflammatory
disease. The specification, however, provides little to no guidance demonstrating that representative compounds across the full scope of Formula I are effective for treating these conditions. Furthermore, the claimed methods are unpredictable because the specification does not demonstrate that any compound of Formula I is suitable for treating, preventing, or curing an MC4R-relted condition, disease, or disorder. Consequently, there is no representative compound from which a person of ordinary skill in the art (POSITA) would reasonably predict that the full scope of Formula I compounds would be effective, and undue experimentation would be required to identify operative compounds. There is one assay described in the specification with data. Applicants do no assert, and it is not art-recognized, that this in vitro assay is correlated to clinical efficacy of the treatment of these diseases. In an unpredictable art, in vitro assays may not be predictive of in vivo efficacy and, thus, may be insufficient alone to establish enablement in the absence of a well-established correlation between the assay and clinical efficacy in the art and/or Applicant’s specification.
c) There is no working example of treatment of any rejected disease in humans or non-human animals.
d) The nature of the invention is clinical treatment of disease with antagonists of MC4R,
which involves physiological activity.
e) The state of the clinical arts for MC4R-related therapies demonstrates that drug development in this field is highly unpredictable, as preclinical receptor activity has not consistently translated into clinical efficacy. For example, several MC4R lead compounds failed in clinical trials because of either insufficient efficacy or safety-related issues. For instance, compound LY2112688 failed as a therapeutic agent because of significant cardiovascular side effects. Therefore, a POSITA would not reasonably expect that a compound demonstrating activity in the disclosed assay would necessarily be effective for treating the claimed MC4R-related diseases. (see Prindle CR et al., (2026) The melanocortin receptors as targets for general obesity: contextualizing clinical failures and analyzing future perspectives. Front. Endocrinol. 17:1797586).
f) The artisan using Applicant's invention would be a physician with a MD degree and
several years of experience.
g) It is well established that "the scope of enablement varies inversely with the degree of
unpredictability of the factors involved", and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833,839, 166 USPQ 18, 24 (CCPA 1970). Consistent with this principle, numerous MC4R-targeted compounds demonstrating promising preclinical receptor activity have failed to consistently translate into clinical efficacy, illustrating the unpredictability of developing therapeutically effective MC4R modulators. As evidenced by Prindle (page 3-13) describing some of the lead compounds do not produce clinically meaningful weight loss at well-tolerated doses, while other terminated due to skin pigmentation. (see Prindle CR et al., (2026) The melanocortin receptors as targets for general obesity: contextualizing clinical failures and analyzing future perspectives. Front. Endocrinol. 17:1797586).
h) The breadth of the claims involves all of the thousands of compounds as well as the
hundreds of diseases embraced by the claims. However, and as mentioned above, the state of the art further demonstrates the unpredictability of MC4R-targeted therapies. As evidenced by Prindle (page 3-14) describing that most MC4R agonist candidates for obesity failed to demonstrate sufficient clinical efficacy due to limited efficacy, adverse effects, or both. The only approved MC4R therapy, setmelanotide, is limited to specific rare genetic obesity disorders and not general obesity. Thus, MC4R activity alone does not establish therapeutic efficacy. Because the specification provides no evidence that the claimed Formula I compounds can prevent, reverse, alleviate, or slow progression of the broad range of conditions as claimed. There is no reasonable basis to conclude that MC4R activity predict therapeutic efficacy for these conditions. Moreover, the art does not demonstrate that MC4R compounds are effective treatment for several of the claimed indications, including malnutrition, hypertension, and depression, as an example. In fact, as evidenced by Prindle, certain MC4R-target compounds have been associated with cardiovascular effects, including increases in blood pressure, further demonstrating unpredictability of relying on MC4R activity alone to achieve the claimed therapeutic outcomes. . (see Prindle CR et al., (2026) The melanocortin receptors as targets for general obesity: contextualizing clinical failures and analyzing future perspectives. Front. Endocrinol. 17:1797586). Moreover, the claims are broad regarding the diseases/conditions being treated, the patient population being treated, and the fact that the claimed methods embrace prevention, palliative treatment, and reversing the state of the diseases/conditions being treated. See Applicant’s definition of “treat”, “treating”, or “treatment” on page 13, lines 8-11 of the specification.
MPEP 2164.0l(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 and undue
experimentation will be required to practice Applicants' invention.
Subject Matter Free of the Art of Record
The subject matter of claim 1 is free of the art of record, and all claims, except claims 33-34, that directly or indirectly depend on claim 1. The closest prior art is Okubo et al. EP 2003131A1. While Okubo teaches MC4 receptor antagonistic effect of compound of formula I, however there is no motivation for a POSITA to modify the teaching of Okubo to arrive at the claimed compound. For example, although Okubo describes aminopyrrolidine compounds with heteroaryl substituents, however, Okubo does not explicitly disclose or suggest the specific substituted aminopyridine-pyrrolidine scaffold of Formula I, including the defined R1 heteroaryl groups, R2, R3 Y1 and Y2, RF, and R7 substitution patterns. Thus, Okubo does not teach or suggest the specific combination of heterocyclic substituents and pyrrolidine substitution required by the claimed compound of Formula I. Claims 1-4, 7, 10, 12, 14, 17, 21-22, 24-25, 29, 31-32 and 38 are allowed; however, claims 33-34 are not allowable until the 112 rejection is overcome.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PIERRE PAUL ELENISTE whose telephone number is (571)270-0589. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm (EST).
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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