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 .
DETAILED ACTION
This office action is in reply to the application 18/709,091 filed on 10 May 2024, 371 of PCT/IB2022/061716 filed on 02 December 2022, with PRO 63/393,043 filed on 28 July 2022 and PRO 63/287,127 filed on 08 December 2021. Claims 3-6, 8, 10 and 13 are amended. Claims 18-20 are canceled. Currently, claims 1-17 are pending.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 15 August 2024 was filed after the mailing date of the application on 10 May 2024. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
Claims 8-17 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. A review of the rejected claim language indicates that this claim is drawn toward “a method of treating a BRAF-associated tumor in a subject in need thereof, comprising administering to the subject the crystalline anhydrous N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluorazetidine-1-sulfonamide, Form 1”. In Applicant’s originally filed specification, they summarize the importance of the BRAF protein as part of the ERK signaling pathway as it regulates and affects cell division and differentiation and the association between BRAF mutation and numerous tumors and their cancers. However, while the Applicant discloses several working examples including in vitro pERK inhibition assays, proliferation assays and drug-like properties including permeability and pharmacokinetics, it does not encompass subjects beyond cells including mammals such as those commonly used in in vivo testing such as mice and rats, those used in toxicology such as dogs or monkeys, much less human. Halle et al. (Defining and targeting BRAF mutations in solid tumors, Curr. Treat. Options in Oncol. 2021, 22, 30, 1-15) teaches that BRAF mutations occur in up to 8% of human cancers, including melanoma, colorectal carcinoma, glioma, thyroid cancer, non-small cell lung carcinoma, cholangiocarcinoma, and several hematologic malignancies (pg. 2 – introduction). This spans a broad breadth of etiologies, patient populations, co-morbidities, and even treatment approaches which are outlined by Halle in several sections. This leads one to conclude that the applicant was not in possession of a method of treating BRAF-associated tumors in a subject to all cancers that are encompassed by claims 8-12 to the extent that broadest reasonable interpretation requires. This necessarily extends to claims 13-17 which claims synergistic therapies with the compound of independent claim 1, Claturafenib. While MEK and EGFR inhibitors Binimetinib and Cetuximab are known in the art, Applicant fails to disclose any working examples of synergistic effects between Claturafenib and any other single agent therapy in the instant specification. Whether the specification shows that the inventor was in possession of the claimed invention is not a single, simple determination, but rather a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structures, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. In contrast, for inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. One of skill in the art would not recognize from the disclosure that the applicant was in possession of a “method of treatment” for the disease as claimed.
Additionally, it is known that there are significant challenges translating biochemical, in vitro, and in vivo studies to a clinical setting, and that not all biochemical, in vitro, and in vivo studies can be directly translated to the clinical setting. Indeed, J. M. McKim (Building a tiered approach to in vitro predictive toxicity screening: a focus on assays with in vivo resistance, Combo. Chem. & High Throughput Scr. 2010, 13, 188-206) emphasizes a truism of the pharmaceutical industry that persists to this day, is the failure of over 90% of promising new drug candidates due to unanticipated adverse effects or a lack of efficacy in humans, contrary to anticipated results based on prior biochemical, cell, or animal models (introduction). As the specification discloses a working example performed in vivo, one of skill in the art would not recognize that the Applicant was in possession of “a method of treatment” of the various diseases and conditions claimed in other models, much less a clinical setting.
Claims 8-17 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 inhibiting pERK and cell viability in vitro in cell lines A375, H1755, NCI-H1666, and WM3629, it does not reasonably provide enablement for treating BRAF-associated cancers in other patients or humans. 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 many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue”. These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP § 2164.01(a).
Upon consideration of the factors discussed below, the examiner concludes that one skilled in the art could not practice the invention without being burdened with undue experimentation based on the information provided by the Applicant. A discussion of these factors as they relate to the pending claims is as follows:
(A) Breadth of claims & (B) Nature of invention –
The Applicant’s claims are broad. For example, claims 8-12 are directed to “a method for treating BRAF-associated cancers in a subject in need…”. The diseases and conditions vary with disparate etiologies, patient populations, and numerous other relevant factors while the instant specification discloses working examples only performed in vitro. As such, one of ordinary skill in the art would not recognize that the evidence provided by the Applicant in the instant specification is “a method of treatment” for any disease or condition claimed considering the possible breadth of what are individually diverse diseases and conditions that can arise from multiple factors, never mind considering the aggregate.
(C) The state of the prior art –
The state of the prior art provides evidence for the degree of predictability in the art and is related to the amount of direction or guidance needed in the specification as filed to meet the enablement requirement. The state of the prior art is also related to the need for working examples in the specification. See MPEP § 2164.05(a). As stated above, Halle teaches the broad range of BRAF-associated cancers and some known treatment approaches, involving numerous associated factors. Therefore, it is reasonable to conclude that the current state of the art is highly unpredictable, indicating that more details, working examples, and guidance would be required to practice the invention as disclosed for the treatment of the diseases and conditions claimed.
(D) The level of one of ordinary skill in the art –
MPEP 2141.03 states (in part), “A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR International Co. v. Teleflex Inc., 127 S.Ct. 1727, 167 LEd2d 705, 82 USPQ2d 1385, 1397 (2007). “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. At 1396, 82 USPQ2d at 1396. The “hypothetical person having ordinary skill in the art' to which the claimed subject matter pertains would, of necessity, have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988) disagreeing with the examiner' s definition of one of ordinary skill in the art (i.e. a doctorate level engineer or scientist working at least 40 hours per week in semiconductor research or development), and finding that the hypothetical person is not definable by way of credentials, and that the evidence in the application did not support the conclusion that such a person would require a doctorate or equivalent knowledge in science or engineering).
These hurdles render application of “a method of treatment” of the diseases and conditions claimed to a very high level of unpredictability. The lack of significant guidance from the present specification makes practicing the claimed invention unpredictable. Where the predictability in the art is low, the Applicant is required to provide greater disclosure and guidance to comply with the enablement requirement. MPEP § 2164.03.
(E)Existence of working examples & (F) Amount of direction or guidance by the inventor –
As previously established by Halle, BRAF-associated cancers are complex and sophisticated processes. Conversely, the specification does not demonstrate, also as previously established, a means to treat all BRAF cancers to subjects in need to the extent that broadest reasonable interpretation requires. Instead, the instant specification only provides in vitro results. Therefore, the applicant has not provided sufficient guidance to enable one of skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims.
(G) Quantity of experimentation needed to make or use the invention –
Taken together, the prior art demonstrates that the disease of BRAF-associated cancers arises from multiple factors and etiologies. This covers a breadth and scope of material that is far from adequately addressed in the instant specification. While the specification demonstrates in vitro assays and drug-like properties, it does not demonstrate how “a compound” would be able to matriculate into a preclinical candidate, much less a new investigational drug with a reasonable chance of success to reach the status as a demonstrative drug containing therapeutically efficacious properties. Even if the compound was not being considered for human treatment, there are, as established by McKim, numerous hurdles that must be overcome for use in the broad category of a patient including the most basic of demonstrating efficacy in vitro and in vivo, which is not a guaranteed, linear progression. This constitutes undue experimentation. Therefore, the lack of working examples commensurate in scope to the claimed invention and the unpredictability in successful application as described by claims 8-17, and as described in the specification, as filed, does not provide enablement for the claimed method of use.
In conclusion, the claimed invention does not provide enablement for the application in the method of use in treating the diseases claimed. Thus, for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation is undue, due to the broad scope of the claim, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of ordinary skill in the art would be forced into undue experimentation to practice the claimed invention.
Allowable Subject Matter
Claims 1-7 are allowed.
Reasons For Allowance
The following is an examiner’s statement of reasons for allowance: the following is a statement of reason for the indication of allowable subject matter: the compound specified in claims 1-7, N-(2-chloro-3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)-4-fluorophenyl)-3-fluorazetidine-1-sulfonamide, also known as PF-07799933 or Claturafenib, is disclosed in Bettendorf et al. (4-oxo-3,4-dihydroquinazolinon compounds for the treatment of BRAF-associated diseases and disorders, WO 2021/250521 A1, 2021; entered into the IDS on 15 August 2024) and applied in Yeager et al. (A next-generation BRAF inhibitor overcomes resistance to BRAF inhibition in patients with BRAF-mutant cancers using pharmacokinetics-informed dose escalation, Cancer Discovery 2024, 14, 1599-1611). Both are subject to the 35 U.S.C. 102(b)(1)(A) exception.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Summary
Claims 1-7 are allowed. Claims 8-17 are rejected under 35 U.S.C. 112(a).
Conclusion
Claims 1-7 are allowed. Claims 8-17 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Allen Chao whose telephone number is (571)272-7001. The examiner can normally be reached Monday - Friday 0700-1300.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H Alstrum-Acevedo can be reached at 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALLEN CHAO/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
Prosecution Insights