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 .
Election/Restrictions
Applicant’s election of Group (I) in the reply filed on 11/06/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant’s election of compound 16024
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and cachexia as the elected species in the reply filed on 11/06/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 1-16 and 22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention/species, there being no allowable generic or linking claim.
Priority
This application is a National Stage Application, filed under 35 U.S.C. 371, of International Application No. PCT/US2021/054804, filed October 13, 2021, which claims the benefit of priority to U.S. Provisional Patent Application Number 63/092,684, filed October 16, 2020; filed October 16, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/30/2023 & 01/24/2025 has been considered by the examiner.
Status of Claims
Claims 1-22 are pending. Claims 1-16 and 22 are withdrawn. Claims 17-21 are examined in accordance to the elected species.
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 17-21 are 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 treating the elected cachexia with compounds of the formula (I)
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, wherein
Y = O;
X = NR and R is H;
R1 = pyridine;
R2 is 2-chloro-substututed benzyl;
R3 is alkynyl as compound (SR16025); and wherein
Y = O;
X = NR and R is H;
R1 = methyl -substituted pyridine;
R2 is alkenyl; and
R3 is alkynyl as compound as compound (SR11466), does not reasonably provide enablement for treating cachexia with all of the compounds encompassed by the formula (I). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are several guidelines when determining if the specification of an application allows the skilled artisan to practice the invention without undue experimentation. The factors to be considered in determining what constitutes undue experimentation were affirmed by the court in re Wands (8 USPQ2d 1400 (CAFC 1986)). These factors are (1) nature of the invention; (2) state of the prior art; (3) level of one of ordinary skill in the art; (4) level of predictability in the art; (5) amount of direction and guidance provided by the inventor; (6) existence of working examples; (7) breadth of claims; and (8) quantity of experimentation needed to make or use the invention based on the content of the disclosure.
(1) Nature of the invention
The claims are directed to treating cachexia with every compound encompassed by the formula (I).
(2) State of the prior art
The state of the art is that compounds SR16024 and SR11465 that fall within the scope of the formula (I)
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, wherein
Y = O;
X = NR and R is H;
R1 = pyridine;
R2 is 2-chloro-substututed benzyl;
R3 is alkynyl as compound (SR16025); and wherein
Y = O;
X = NR and R is H;
R1 = methyl -substituted pyridine;
R2 is alkenyl; and
R3 is alkynyl as compound (SR11466) and are glucocorticosteroid antagonists can be effective to treat cachexia. (See Jin et al, Morley et al, and Clark et al of the obviousness rejection below). Moreover, Jin teaches compounds 14a falling within the scope of the formula (I) wherein
Y = O;
X = NR and R is H;
R1 = methyl -substituted pyridine;
R2 is a C1-alkyl
R3 is alkynyl as compound 14a; wherein
Y = O;
X = NR and R is H;
R1 = methyl -substituted pyridine;
R2 is a C2-alkyl
R3 is alkynyl as compound 14b; wherein
Y = O;
X = NR and R is H;
R1 = methyl -substituted pyridine;
R2 is a C1-allyl
R3 is alkynyl as compound 14c that are glucocorticosteroid agonists. Thus, one cannot ascertain whether the instant invention is of use of all compounds of the formula (I) can be predicted to treating cachexia.
(3) Level of one of ordinary skill in the art
The level of skill in the art is deemed to be high, generally that of a medical Doctor specializing in the field of medical oncology, palliative care, nutrition science, and rehabilitation.
(4) Level of predictability in the art
The art pertaining to the use of every compound of the formula (I) to treat cachexia is highly unpredictable. Specifically, namely Ni et al (Cancer Management and Research 2020:12 5597–5605) teaches cachexia is a multifactorial disease characterized by weight loss via skeletal muscle and adipose tissue loss, an imbalance in metabolic regulation, and reduced food intake. (See Abstract.) Moreover, Ni teaches glucocorticoids, such as the drugs prednisone acetate and dexamethasone, inhibit pro-inflammatory cytokines like TNF-α and IL-1 to increase appetite and improve nausea, but cannot eliminate muscle loss. (See Section 9 of the left column of page 5601.)
In sum, a person of ordinary skill in the art would not expect that compounds of the formula (I) bearing certain substituents such as compound 14a, 14b, and 14c as glucocorticosteroid agonist to treat cachexia (muscle wasting).
(5) Amount of direction and guidance provided by the inventor
The claims encompass a vast number of compounds of the formula (I). Applicant’s limited guidance does not enable the public to use every claimed compound of the formula (I) for treating cachexia. There is no directional guidance for the treatment of cachexia with every compound of the formula (I). Hence, there is no enablement for every compound of the formula (I) can treat cachexia.
(6) Existence of working examples
The claims encompass a vast number of compounds of the formula (I) that lacks the utility. Applicant’s limited working examples do not enable the public to use such broad generic formula (I) to treat cachexia. While Applicant’s claims encompass a plethora of possible compounds of the formula (I), the specification only provides guidance of compound SR16024 and SR11466 the treatment of cachexia.
(7) Breadth of claims
The claims are extremely broad due to the vast number of possible compounds of the formula (I).
(8) Quantity of experimentation needed to make or use the invention based on the content of the disclosure
The specification does not enable any person skilled in the art to which it pertains to make and use the invention commensurate in scope with the claims because using all compounds of the formula (I) for the treatment of cachexia. In particular, the specification fails to enable the skilled artisan to practice the invention without undue experimentation to use all possible compounds of the formula (I) for the treatment of cachexia. Furthermore, based on the unpredictable nature of the invention, the state of the prior art, and the extreme breadth of the claims, one skilled in the art could not perform the claimed invention without undue experimentation
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.
Claims 17-21 are rejected under 35 U.S.C. 103 as being unpatentable over Jin et al (Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 2, 15 January 2017, Pages 347-353) in view of Morley et al (The American Journal of Clinical Nutrition, Volume 83, Issue 4, April 2006, Pages 735-743) and Clark et al (WO2005/087769 A1).
Jin teaches a synthesis of novel steroidal agonists, partial agonists, and antagonists for the glucocorticoid receptor. (See Title.) Moreover, Jin teaches compound 14h
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. Compound 14h with excellent antagonist action is the same as the elected compound. Jin also teaches after stimulation with various compounds, the Fkbp5 mRNA levels in these muscle fibers generally reflected the GR activity profiles observed in the luciferase reporter assays where substitution of the beta-directed hydroxyl with small alkyl groups led to a 40-fold increase in Fkbp5 mRNA levels (compare 8b to 14a–c), indicating a potent, full GR agonist-like effect. In contrast, substitution of this hydroxyl with bulkier alkyl groups did not have a striking effect on Fkbp5 expression (compare 8b to 14a-h), consistent with a GR antagonist profile. Compound 14e is noted to have a substantial decreased Fkbp5 mRNA levels in mouse C2C12 myotubes (See Tables 1-4, third paragraph of the left column bridging second paragraph of the right column of page 352.) The lack of effect of Fkbp5 expression with compound 14e suggests that compound 14e would not affect muscle fibers or wasting. Additionally, Jin teaches these novel steroidal based GR agonist 8f and 10d, partial agonists 8b, 8e, 10e, 10f, 14a, 14b, 14c and 16, and antagonists 8a, 8c, 8d, 8g, 10g, 14d, 14e, 14f, 14g and 14h were successfully synthesized. Glucocorticoids with dissociated phenotypes in vitro have shown reduced anti-inflammatory/transactivation ratio in vivo and in humans. This may reflect the variety of glucocorticoid target tissues that contribute to both inflammatory cytokine secretion and metabolic parameters such as glucose disposal, suggesting anti-inflammatory effect of these compounds. (See third paragraph of the left column of page 353.)
Jin does not teach administration of compound 14e for treating cachexia.
Morley teaches the major cause of cachexia appears to be cytokine excess. Other potential mediators include testosterone and insulin-like growth factor I deficiency, excess myostatin, and excess glucocorticoids. (See Abstract.) Moreover, Morley teaches. excessive elaboration of proinflammatory cytokines such as interleukin (IL) 1, IL-2, interferon ϒ, and tumor necrosis factor α (TNF-α) is probably the most common cause of cachexia observed in acutely ill patients. Cytokines activate nuclear transcription factor κB (NF-κB), which results in decreased muscle protein synthesis. (See first paragraph of the right column of page 735.)
Clark teaches a method of treating a disorder or condition through antagonizing a glucocorticoid receptor, the method comprising administering to a subject in need of such treatment, an effective amount of the compound of the formula (I). (See claim 30.) Moreover, Clark teaches GR modulators may also affect a wide variety of disease states, such as cachexia. (See paragraph [0066].)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer the compound 14e in a pharmaceutical composition to as subject to treat cachexia. One would have been motivated to do so, because Jin teaches compound 14e exhibits great anti-inflammatory effect and antagonist effect for the glucocorticoid receptor and also because Morley teaches cachexia is characterized by excess of glucocorticoids and excess of proinflammatory cytokines, and also because Clark teaches GR modulators including GR antagonists may also affect a wide variety of disease states, such as cachexia. One would have had a reasonable expectation of success of administering compound 14e as an antagonist of glucocorticoid receptor and an anti-inflammatory agent in a pharmaceutical composition to treat cachexia.
Conclusion
Claims 17-21 are not allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEAN P CORNET whose telephone number is (571)270-7669. The examiner can normally be reached Monday-Thursday from 7.00am-5.30pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached at 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628