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 1-10 are pending.
Priority
Instant application 18/282,147, filed 09/14/2023 claims priority as follows:
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Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
All references from IDS received 02/06/2024 have been considered unless marked with a strikethrough.
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 1-5 and 9-10 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.
Applicants claim a compound of Formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof:
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In view of the definitions recited for Z1, Cy1, Z2, and Cy2, the scope of the claims covers a massive number of compounds under this genus and includes very different compound scaffolds with very different structural features which are not well supported by the examples in the specification. Stated differently, the specification of this application does not describe the manner and process of making and using the full scope of the claimed compounds, in such full, clear, concise, and exact terms. There appear to be about 33 compounds disclosed (made and tested) in the specification (see, e.g. the compounds recited in claim 8; or in the specification at pages 7-8). Of the 33 compounds, 23 appear to be selective estrogen receptor degraders (SERDs); 8 appear to be covalent antagonists (SERCAs); and 2 appear to be Proteolysis Targeting Chimeras (PROTACs) that target the estrogen receptor for degradation.
No other compounds are disclosed. In the parts of the molecules where no or very little variation are disclosed, the person having ordinary skill would reasonably expect that these are part of the pharmacophore important for the activity of the compounds. Note in particular that the following moieties have the same meaning in all of the examples, and therefore appear to be essential for the compounds’ activity:
R1 is methyl;
R2 is hydrogen;
R3 represents -CH2CR31R32R33, wherein R31, R32, and R33 are defined under the preferred options in claim 4;
Z1 is a bond;
Cy1 is phenyl or pyridinyl, optionally substituted with F or methoxy; and
Z2 and Cy2 are essentially as defined in claim 4.
The ordinary skilled chemist would not be able to predict which of the widely varied compounds (e.g. compounds where Cy1 is any arylene or heteroarylene having as few as 3 and as many as 14 atoms) would have similar activity, or any activity, compared to the examples in the specification. No activity data has been provided for compounds where Cy1 is not a phenyl or 2-pyridyl moiety. This logic extends to the other variables identified above which are the same in every example provided (e.g. Z1 is always a bond, R1 is always methyl, etc.).
The invention is in a class of inventions which the CAFC has characterized as "the unpredictable arts such as chemistry and biology." Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). The state of the art is that “chemical reactions are known as unpredictable”. In re Marzocchi, et al., 169 USPQ 367, 370 (CCPA 1971); In re Fisher, 166 USPQ 18, 24 (CCPA 1970).
“The examples and description should be of sufficient scope as to justify the scope of the claims”. See MPEP § 608.01(p). If a representative number of adequately described species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, para. 1 (MPEP 2163).
Applicant’s assumption that the very structurally different compounds included in the claims will work the same way is scientifically unreasonable. It is not possible for one of ordinary skill in the art to extrapolate, from the limited data in the specification, the structural features required in the claimed compounds for the claimed activity. Thus, Applicant has only properly described how to use those compounds that have been particularly tested and found efficient for the claimed use. Applicant has not described with reasonable clarity how to make and use the full scope of the claimed invention.
Close prior art which was identified in a search for the claimed compounds is Scott et al. (Expert Opinion on Therapeutic Patents, vol. 32, no. 2, Feb. 2022, pp. 131–51). Scott is a patent review of SERDs and SERCAs disclosed between the period January 2015 to June 2021. Key compounds include those disclosed in Fig. 1 (page 133):
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Note that AZD9833 is a compound which has similar structure to the instantly claimed compounds, particularly compound 5 in claim 8. However, AZD9833 differs from the claims by the identity of the 5-membered ring in the tricyclic core (pyrazolyl vs oxazolyl). Other SERDs having similar structure are disclosed in FIG. 17 (page 140):
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The claimed moieties identified previously (e.g. Cy1, Z1, R1, etc.), which are the same in all examples of the instant application, are also the same in the compounds disclosed in the prior art. Therefore, the prior art does not provide the structure-function correlation which is missing from applicant’s disclosure to support the entirety of the claimed genus. Instead, the prior art provides additional evidence that a person having ordinary skill would reasonably expect that the unchanging moieties are part of the pharmacophore, and are therefore important for the activity of the compounds.
"A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)”. The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 "merely by clearly describing one embodiment of the thing claimed." LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005). The issue is whether a person skilled in the art would understand applicant to have invented, and been in possession of, the invention as broadly claimed.
A need for greater disclosure derives from the fact it is not obvious from the disclosure of one species, what other species will work. Generally speaking, the Courts recognize that predictability in chemical arts is low enough to require a highly detailed disclosure. Unpredictability arises in chemical arts because subtle changes in molecular structure may greatly impact a compound's structure-activity relationship, pharmacologic activity, and/or biologic profile. In drug development, the skilled artisan would not be able to easily extrapolate the biological activity from a single example or limited disclosure without more instruction. These considerations support a requirement for a disclosure with a high level of detail. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required.
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate"). Accordingly, it is deemed that the specification does not describe in sufficient detail the genus of compounds in the claims and how to make them and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Claim 10 is 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 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.
The specification, while being enabling for the treatment of estrogen receptor-dependent or -mediated breast cancer in a mammal, does not reasonably provide enablement for the treatment of any estrogen receptor-dependent or -mediated disease in a mammal. 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.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Nature of the invention:
The invention is drawn to the administration of a compound having Formula (I):
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to treat an estrogen receptor-dependent or -mediated disease in a mammal. The compounds are disclosed as degraders of estrogen receptor activity.
Breadth of the claims:
The claims are broadly directed to the use of the compound for the treatment of all diseases which are dependent on or mediated by estrogen receptors, known today or that may be discovered in the future.
Level of ordinary skill in the art:
The artisans using applicant’s method would be a collaborative team of medicinal chemists, pharmacologists, and/or healthcare practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience.
The level of skill in the art is high; however, due to the unpredictability in the pharmaceutical arts, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro or in vivo screening to determine which compounds exhibit the desired pharmacological activity and which diseases would benefit from this activity.
State of the prior art and predictability in the art:
With respect to the role of estrogen receptors in disease recognized by the prior art, see for example Jia et al. (Best Practice & Research Clinical Endocrinology & Metabolism, vol. 29, no. 4, Aug. 2015, pp. 557–68). Jia discloses (see abstract) that Estrogen receptors alpha (ERα) and beta (ERβ) are transcription factors that are involved in the regulation of many complex physiological processes in humans. Abnormal ER signaling leads to development of a variety of diseases, such as cancer, metabolic and cardiovascular disease, neurodegeneration, inflammation, and osteoporosis. The role that estrogens and estrogen receptors play in these diseases is varied and approaches to treating each disease are not the same.
See also Burns et al. (Archives of Toxicology, vol. 86, no. 10, Oct. 2012, pp. 1491–504).
Burns discloses that a myriad of physiological processes in mammals are influenced by estrogens and the estrogen receptors (ERs), ERα and ERβ (abstract); and that estrogens and ERs mediate a number of disease states including human cancers (breast, ovarian, colorectal, prostate, and endometrial), endometriosis, fibroids, and cardiovascular disease. The loss or overexpression of the ERs contributes to disease development and progression.
Therefore, estrogen receptors were known in the prior art to mediate a number of effects, and to be associated with many diverse metabolic, cardiovascular, neurodegenerative, reproductive, and inflammatory diseases, in addition to human cancers. However, the instant application only provides support for the treatment of breast cancer by one mechanism of action (ER degradation).
Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
That a single compound or class of compounds can be used to treat all disorders dependent on or mediated by estrogen receptors is an incredible finding for which Applicant has not provided sufficient supporting evidence.
The instant specification discloses only one example of an assessment of the claimed compound against an ER-mediated disease, specifically an in vitro assessment against human breast cancer cell line MCF-7 (Test Example 2). No working examples of other diseases which are dependent on or mediated by estrogen receptors are disclosed.
See MPEP 2164.02 (“Compliance with the enablement requirement of 35 USC 112, first paragraph, does not turn on whether an example is disclosed ... Lack of a working example, however, is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.”).
The amount of direction provided and working examples:
The only direction or guidance present in the instant specification is the disclosure of diseases applicant considers as treatable by the claimed compound, and evidence (limited to breast cancer) for the efficacy of the claimed compound.
Quantity of experimentation needed to use the invention based on the content of the disclosure:
The quantity of experimentation needed is undue experimentation. One of skill in the art would need to determine which disorders, of all the disorders associated with estrogen receptors, would actually be treated by the claimed compound.
A person having ordinary skill in the art at the time the invention was made would be faced with an undue amount of experimentation to use the compounds of Formula (I) according to the full scope of the claimed method.
Therefore claim 10 is rejected.
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 1-2, and 4-7, and 9-10 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, the claims contain numerous instances of a broad recitation, and the claim also recites the word “preferably” followed by a narrower statement of the limitation. For example, claim 1 recites the limitation
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and also recites “preferably
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”. See also “preferably R4 is H, a halogen…”). Please note that this issue (where a broader limitation is set forth, followed by “preferably” and a narrow statement of the limitation) appears in multiple instances in claims 1, 2, 4, 5, and 6.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The issue should be corrected in each instance where it appears in claims 1, 2, 4, 5, and 6. Claims 7 and 9-10 depend from claims which are indefinite and fail to resolve the issue identified above. Therefore claims 1-2, and 4-7, and 9-10 are rejected.
Allowable Subject Matter
Claim 8 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Claims 1-7 and 9-10 are rejected. Claim 8 is objected to.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kyle Nottingham whose telephone number is (571)270-0640. The examiner can normally be reached M-F from 10:00 am - 6:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton 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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/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621