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 .
Drawings
The drawings are objected to because:
Drawings comprise text that is upside down and text that is illegible. Specifically, In Figure 2, the lines, markers and axis identifiers are too smudged, and the font is too small to be legible.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
References in The Specification
Specification comprises references that have not been listed in the IDS. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112
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 2-21 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 method comprising administering to a subject an effective amount of TEAD inhibitor on each of the first 3 days of a 7 day treatment cycle.
With regards to TEAD inhibitor, it is unclear which pharmaceutical agents are within the scope. Even when limited to YAP/TAZ transcriptional coregulators, art teaches multiple agents with different mechanisms of action. Some act on various upstream proteins, some act on directly on TEAD family of transcription factors or YAP/TAZ, some act on downstream targets (See Pobbati et al., Theranostics 2020, 10(8), 3622-3635). It’s unclear if the TEAD inhibitors in the claims are compounds that act directly on TEAD or if upstream and downstream targets are within the scope of the claim.
With regards to treatment schedule, the claim language “comprising” allows for daily administration of the TEAD inhibitor. In daily administration, the agent is administered on each of the first 3 days, which meets the claim limitation. The claim is not limited to no administration on days 4-7. In view of the description, and in order to advance examination, Examiner will interpret the claim as being directed to administration on days 1-3 and no administration on days 4-7 of a 7 day treatment cycle.
Claim Rejections - 35 USC § 112
112(a) – Scope of 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 2-21 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 a method of treating mesothelioma cancer where the cancer comprises hyperactivation of YAP and/or TAZ by administering compound A, does not reasonably provide enablement for the broad scope of “cancer” or TEAD dependent cancer by administration of a broad genus of “TEAD inhibitor”. 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. This is a scope of enablement rejection.
To be enabling, the specification of the patent application 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 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
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 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). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 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 of those in the art
The invention is directed to a method of treating any cancer. While some claims limit the cancer to TEAD dependent cancer, this limitation does not actually limit the scope of the diseases. TEAD transcription factors are widely and broadly expressed across most tissues and organs. This means most cells including cancer cells depend on expression of TEAD to function properly. Based on the information provided in the specification, the types of cancers that can be treated by inhibition of TEAD are ones that comprise hyperactivation of TAP/TAZ resulting in their translocation to the nucleus and interaction with TEAD.
With regards to TEAD inhibition in cancer therapy, art teaches numerous pathways that are modulated by a vast variety of agents (Pobbati et al., Theranostics 2020, 10(8), 3622-3635). Pobbati teaches 3 groups of inhibitors that act upstream, at TEAD, and downstream. Each of the 3 groups comprise subgroups acting on specific targets. Group I alone comprises Intracellular kinases, Mevalonate pathway inhibitors, Cellular energy stress modulators, Actin modulators, Epigenic modulators, and phosphatase inhibitors, each being a genus comprising multiple agents that carry out the required function. Pobbati also teaches major challenges including various toxicity issues (page 3631) and identification of subjects that respond to treatment. Pobbati also teaches that there are tumors where YAP/TAZ or TEAD levels have no prognostic significance (page 3631, column 2, last paragraph).
In view of Pobbati, it appears that treatment of cancers with TEAD inhibitors is limited to treatment of specific cancers with a specific TEAD inhibitor that has been demonstrated to be effective at slowing cancer cell proliferation in said cancers. Applicants have demonstrated antitumor activity of compound A in mesothelioma. Applicants have also demonstrated improved safety profile of Compound A when administered according claimed 3 days on - 4 days off treatment cycle. No other TEAD inhibitor or any other cancer type has been tested.
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicant’s invention would generally be a physician with a M.D. degree and several years of experience.
The factor is outweighed, however, by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); Ex parte Sudilovsky 21 USPQ2d 1702 (Applicant’s invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain). As illustrative of the state of the art of treating any cancer, the examiner cites Kunnumakkara et al (“Cancer drug development: The missing links”).
Kunnumakkara, cited for evidentiary purposes, teaches cancer is a group of more than 200 neoplastic diseases caused by diverse deregulated cell signaling cascades (page 633, left, 1st paragraph); consumption of tobacco and alcohol, obesity, insufficient physical activity, exposure to ultraviolet radiation, and various dietary factors which include insufficient fruit, non-starchy vegetables, and fiber; red/processed meat are predicted to be strongly associated with the risk of diverse cancer types; cancer occurs as a result of the dysregulation of as many as 500 different genes which may happen over a very long duration of time (20–30 years) till the symptoms become apparent (page 633, right, last bridge paragraph). Kunnumakkara further teaches there exists a missing connection between preclinical data and clinical findings; although, a significantly huge amount of money is spent in the pre-clinical settings for target validation and drug optimization, most of the therapies fail in the clinical trials till date; this can be due to the reason that the models used in the pre-clinical setting are not the adequate ones to effectively mimic human responses (page 664, right, 2nd paragraph); although highly convenient, cancer cell line models are associated with several limitations as well; for example, existence of genomic instability which may result in differences between the original tumor and the respective cell line, culture conditions that can alter the morphology, gene expression pattern, genomic profile, cellular pathways and culture environment from that of the original tumor, loss of natural tumor heterogeneity; the generic transformations that occur upon culturing of the cancer cells are not restored when regrown in vivo; and cancer cells in the in vitro condition grow in absence of stroma which include lymphatic vessels and blood, associated fibroblasts and immune cells, and lack a complex extracellular matrix; therefore, in vitro data often exhibits fundamental mismatch with those obtained from clinical findings and hence this can be regarded as one prime reason behind the failure of novel drug development (page 665, last bridge paragraph). Kunnumakkara teaches the foremost shortcomings of the use of animal models are their inability to recapitulate the link between the tumor and its microenvironment completely and the requisite of an immunocompromised host; basically, these animal models do not have the ability to reflect all the features of human cancer impeccably. Kunnumakkara teaches that despite the advances in understanding of cancer biology and deriving different novel therapeutic targets, the translation of these understanding into therapies is poor due to higher failure rate (90%). The high failure rate could be due to non-consideration of factors such as clinical translation, drug delivery, drug pharmacokinetics, pre-clinical models, and tumor physiology, which are critical factors.
As illustrative of the state of the art of the Hippo pathway, which YAP/TAZ, TEAD, Nf2, LATS1, and LATS2 are implicated in, the examiner cites Cunningham (Clinical Science (2022); 136; 197–222). Cunningham teaches that the Hippo pathway is modulated by genes and activators including LATS1/2, Yap, and Tas (p. 197, para. 1 of Introduction, lines 1-10). This pathway and alterations thereof are implicated in numerous diseases and conditions, including embryogenesis and a wide range of cancers. Overexpression in particular is implicated in a number of cancers (p. 202, Table 1). The inhibition of YAP and YAP/TAZ-TEAD binding is under-developed, especially in vivo, as although inhibition of YAP-TEAD transcription inhibits tumor growth in murine models, there is cytotoxicity associated with this inhibition independent of its effectiveness on cancers (p. 207, para. 3). The authors note that “overall, the context-dependent role the Hippo pathway plays in immune oncology warrants further examination in order to uncover the interplay and complexities between Hippo pathway components and the immune system” (p. 209, para. 3, lines 5-7).
These articles plainly demonstrate that the art of developing and testing anticancer drugs including YAP inhibitors, particularly for use in humans, is extremely unpredictable, particularly in the case of a single compound or genus of compounds being used to treat any and all diseases wherein YAP overexpression, YAP amplification, or YAP/TAZ-TEAD interaction is implicated, as well as treating any and all cancers or tumors harboring one or more YAP/TAZ fusions; one or more NF2/LATS1/LATS2 truncating mutations or deletions; or one or more functional YAP/TAZ fusions.
2. The breadth of the claims
Claims are very broad in terms of the types of cancers being treated and in terms of agents used for treatment. These elements have discussed above.
3. The amount of direction or guidance provided and the presence or absence of working examples
Specification provides 2 examples; both are directed to treatment of mesothelioma by administration of compound A. No other cancers or therapeutic agents have been exemplified.
4. The quantity of experimentation necessary
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that any TEAD inhibitor could be predictably used to treat all cancers even if the scope is limited to those mediated by YAP overexpression, YAP amplification, and YAP/TAZ-TEAD interaction. Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but compensation for its successful conclusion and 'patent protection' is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" (42 USPQ 2d 1001, Fed. Circuit 1997).
As noted above, the specification in view of the prior art provides no experimental support for the treatment of any cancer including the genus in which YAP overexpression, YAP amplification, or YAP/TAZ-TEAD interaction is implicated. A review of the state of the art fails to reveal any TEAD inhibitor can be used to treat any cancer. Determining if any particular claimed compound would treat any particular cancerous disease state would require synthesis of the compound, formulation into a suitable dosage form, and subjecting it to clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment. This is undue experimentation given the limited guidance and direction provided by Applicants. As noted supra, even in vitro and in vivo assays do not always correlate to efficacy in humans and are not generally predictive of clinical efficacy.
Accordingly, claims 2-21 do not comply with the enablement requirement of 35 U.S.C. 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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.
Claims 2-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 31, 52, 53 and 54 (claim set dated 9/24/24) of copending Application No. 18/687616 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. While all of the limitations of current claim 2 are not found in a single claim of the ‘616 application, all of the limitations are nonetheless present:
Claim 1 is directed to a method of treating cancer comprising administering to a subject a TEAD inhibitor.
Claim 31 recites the currently claimed Compound A as the TEAD inhibitor
Claims 52 and 53 recite specific cancers and TEAD dependent cancer.
Claim 54 recites a method of administration comprising administration on the first 3 days of a 7-day treatment cycle.
With regards to specific doses, claim 1 recites administration of an effective amount of a TEAD inhibitor. A skilled artisan would have found it obvious to determine by routine experimentation the effective amount of TEAD inhibitor to administer.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 2-21 are pending
Claims 2-21 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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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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/YEVGENY VALENROD/Primary Examiner, Art Unit 1628
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