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 1-8, 10, and 13-15 are pending.
Priority
Instant application 18/012,278, filed 12/22/2022 claims priority as follows:
PNG
media_image1.png
104
649
media_image1.png
Greyscale
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
All references from IDS(s) received 6/10/2024, 11/7/2024, 4/11/2025, 6/30/2025, and 7/28/2025 have been considered unless marked with a strikethrough.
Response to Amendment/Arguments
The amendment filed 12/04/2025 has been entered. Applicant has amended claim 8. Claims 9, 11, and 12 have been cancelled.
Claims 9, 11 and 12 were objected to and/or rejected in the Non-final rejection mailed 09/04/2025. Claims 9, 11 and 12 have been canceled, rendering the objection and/or rejection(s) over claims 9, 11 and 12 moot.
Claim 8 was objected to in the Non-final rejection mailed 09/04/2025. In view of the amendment filed 12/04/2025, applicant has overcome the objection. Therefore, the objection to claim 8 is withdrawn.
Claims 1-7, 10, and 13-15 were rejected under 35 U.S.C. 112(b) in the Non-final rejection mailed 09/04/2025. In view of the arguments filed 12/04/2025, applicant has overcome the rejection. Therefore, the rejection of claims 1-7, 10, and 13-15 is withdrawn. In particular, with respect to the term “CBP/p300 bromodomain inhibitor”, applicant stated:
PNG
media_image2.png
104
584
media_image2.png
Greyscale
;
and with respect to the term “EGFR inhibitor”, applicant stated:
PNG
media_image3.png
103
582
media_image3.png
Greyscale
Claims 1-8, 10, and 13-15 were rejected under 35 U.S.C. 112(a) in the Non-final rejection mailed 09/04/2025. However, upon further consideration, additional grounds for rejection under section 112(a) were identified. See the rejection under 35 U.S.C. 112(a) which has been modified to include the additional grounds further below.
Claim Rejections - 35 USC § 112(a) - New
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 1-8, 10, and 13-15 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 claim(s) 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.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), the following factors are considered 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.
Breadth of the claims:
The claims are broadly directed to the use of any “EGFR inhibitor”, known today and those that may be discovered in the future, to a subject with NSCLC exhibiting any “oncogenic alteration” in the EGFR. The breadth of claim 1 is substantial along two axes.
First, with respect to the EGFR alteration, the specification itself defines “oncogenic alteration in the EGFR” broadly to encompass deletions, insertions, duplications, amplifications, and base mutations in the EGFR gene (US 20230255966 A1, [0060], [0012]).
Second, with respect to the EGFR inhibitor, claim 1 recites “an EGFR inhibitor” without structural or mechanistic limitation. This encompasses small molecule TKIs (reversible and irreversible), monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, and any future EGFR-targeting agent. The specification provides a list of over 40 EGFR inhibitors spanning all of these mechanistic classes (US 20230255966 A1, [0021]).
Nature of the invention:
Applicant discloses a method comprising administering CBP/p300 bromodomain inhibitors, i.e. bromodomain inhibitors that selectively bind bromodomains of CBP/p300, in combination with EGFR inhibitors to provide effective treatment of NSCLC exhibiting altered EGFR oncogenicity. According to the specification, CBP/p300 bromodomain inhibitors, if administered alone, do not affect the cellular proliferation of NSCLC cells exhibiting an oncogenic alteration in the EGFR. The EGFR inhibitor when administered alone exhibited an effect, but that effect decreased over time, likely due to the development of resistance to the EGFR inhibitor.
The present application discloses that the combination of the two inhibitors described above results in an unexpected effect. In particular, the present application demonstrates that CBP/p300 bromodomain inhibitors (Compound A, Compound 00030, Compound 00071, Compound C, CCS1477, FT-6876, GNE-781) when administered in combination EGFR inhibitors (gefitinib and octitinib) are more effective in treating NSCLC exhibiting an oncogenic alteration in EGFR than either agent is alone.
The claimed therapeutic benefit is a biological response that the specification itself characterizes as “surprising” (e.g., para. [0009], [0071]). The specification further acknowledges that “it is not possible to assign a single function to the [CBP/p300] proteins in a given cellular process” and that “the context of the specific disease and the specific cancer type will be decisive” (US 20230255966 A1, [0069]).
State of the prior art and predictability in the art:
At the time of filing, it was well-established that different EGFR mutations respond differently to EGFR inhibitors. For example:
Exon 19 deletions and L858R are the classic “sensitizing” mutations that respond well to first- and third-generation TKIs, but even between these two mutation types, clinical outcomes with EGFR TKIs differ. See LEONETTI (British Journal of Cancer, vol. 121, no. 9, Oct. 2019, p. 725–37; cited previously). LEONETTI teaches that (page 1, first para.):
“Somatic, activating mutations in the tyrosine kinase domain of EGFR are present in about 15% of Caucasian and nearly 50% of Asian patients with advanced NSCLC. Almost 90% of these mutations consist of deletions in exon 19 or L858R point mutations within exon 21.”
LEONETTI additionally teaches that currently, osimertinib is the only third-generation EGFR-TKI approved by major regulatory agencies for treatment of T790M-positive patients who have progressed on first- or second-generation EGFR-TKIs. However, despite the robust clinical activity exerted by osimertinib, patients inevitably develop secondary resistance to this treatment, which poses a significant challenge due to the paucity of post-osimertinib pharmacological options available to date (page 725, right column).
Exon 20 insertions are known to be largely resistant to standard EGFR TKIs, including gefitinib and osimertinib, which are the only two EGFR inhibitors tested in the specification. This resistance is due to steric changes in the drug binding pocket that reduce TKI affinity. See WANG (Translational Cancer Research, vol. 9, no. 4, Apr. 2020. tcr.amegroups.org, https://doi.org/10.21037/tcr.2020.03.10). WANG teaches that (page 1, abstract):
“EGFR exon 20 insertion (EGFR Ex20Ins) is the third most common type of EGFR mutation. Currently, studies on EGFR Ex20Ins are relatively scarce and limited. The frequency of EGFR Ex20Ins mutations in NSCLC was 1–10%. Patients harboring EGFR Ex20Ins exhibited similar clinical characteristics except for poorer prognosis as compared to patients with sensitizing mutations in EGFR. Conventional TKIs have poor efficacy in a majority of EGFR Ex20Ins subtypes. Chemotherapy remains the preferred treatment for advanced NSCLC patients harboring EGFR Ex20Ins.”
Additionally, WANG addresses different classes of EGFR TKIs under “treatments” (pages 2984-2985):
Preclinical experiments have shown that clinically achievable doses of neither first-generation EGFR TKIs (gefitinib and erlotinib) nor second-generation EGFR TKIs (afatinib, dacomitinib, and neratinib) are effective for most of the EGFR exon 20 insertion mutants…The curative effect of osimertinib in metastatic NSCLC patients with EGFR exon 20 insertion mutation has yet to be fully assessed.
Uncommon mutations such as G719X, S768I, and L861Q each have distinct and variable TKI sensitivity profiles that differ from the above-mentioned sensitizing mutations. See, for example, TIANLI (Translational Lung Cancer Research, vol. 8, no. 3, June 2019).
EGFR amplification and kinase domain duplications are mechanistically distinct from activating point mutations and insertions/deletions, involving gene copy number changes rather than altered protein structure. See, for example, JINGUANG (International Journal of Cancer, vol. 144, no. 11, June 2019, pp. 2677–82).
With respect to the CBP/p300 bromodomain inhibitor component, the prior art HOU (BMC Cancer, vol. 18, no. 1, June 2018, p. 641; cited in Specification at para. [0003]) described the role of p300 in NSCLC proliferation, migration, and invasion, but through shRNA-mediated knockdown of the entire p300 protein, which is a fundamentally different mechanism than the selective bromodomain inhibition claimed here. Moreover, the paper appears to have been retracted.
See also ZHANG (Biochemical Pharmacology, vol. 175, May 2020, p. 113914; cited in IDS). ZHANG teaches that downregulation of CBP or p300 enhanced apoptosis upon TRAIL stimulation in EGFR-TKI-resistant NSCLC cells, and CBP/p300 inhibitor 51 (A-485) upregulated anti- and pro-apoptotic genes at mRNA level (page 113914, abstract). However, A-485 alone did not induce NSCLC cells apoptosis (page 14, left side). When treated with a combination of TRAIL and A-485, the number of apoptotic cells were significantly increased, suggesting A-485 as a TRAIL-sensitizer (page 4, right side). However, TRAIL (tumor-necrosis factor related apoptosis-inducing ligand, CD253) is a fundamentally different cancer therapy and is not an EGFR inhibitor.
Therefore, the prior art did not appear to teach that selective bromodomain inhibition of CBP/p300 would potentiate EGFR inhibitor efficacy in any EGFR mutation context, let alone across diverse mutation types.
In view of the state of the art identified above, the skilled artisan would be faced with a high degree of unpredictability in determining which NSCLC mutation populations, beyond those demonstrated in the working examples, would benefit from the combination(s) claimed; and in determining which EGFR inhibitors would actually achieve the desired combination benefit for the patient populations encompassed by the instant claims.
Pharmacological activity in general is a very unpredictable area. Note also 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).
Further, cancer treatment is a field of high unpredictability. The specification itself describes the combination effect as “surprising” (US 20230255966 A1, para. [0009]), noting that CBP/p300 bromodomain inhibitors have no effect on NSCLC cell proliferation when administered alone, yet potentiate EGFR inhibitor efficacy when combined. This result could not have been predicted from the prior art and, by extension, the generalizability of this surprising result across different EGFR mutation contexts cannot be predicted from the limited data presented. Moreover, the specification’s acknowledgement that “it is not possible to assign a single function” to CBP/p300 in a given cellular process and that “the context of the specific disease and the specific cancer type will be decisive on how CBP/p300 are involved, if they are involved at all” directly undermines any argument that the combination effect can be reliably predicted across the diverse EGFR mutation types encompassed by the claims (US 20230255966 A1, [0069]).
Level of ordinary skill in the art:
The artisans using applicant’s method would hold an advanced degree in oncology, pharmacology, or a related discipline, and possess several years of professional experience, with some familiarity for EGFR-mutant NSCLC biology and therapeutics. While this person would possess a high level of skill, that skill would underscore the unpredictability of extending the specification’s results beyond the tested mutation types. A skilled artisan would be aware that, for example, exon 20 insertions respond differently to EGFR TKIs than exon 19 deletions, that EGFR-amplified tumors present distinct therapeutic challenges, and that the combination benefit observed in one mutational context cannot be assumed to apply in another without supporting evidence.
The amount of direction provided and working examples:
With respect to EGFR alteration scope, the specification provides substantial direction for the combination therapy in the context of exon 19 deletions (del E746-A750 and del 747-E749) treated with gefitinib or osimertinib, and for the T790M resistance mutation treated with osimertinib. However, the specification provides no direction for any other EGFR mutation type. While the specification lists numerous EGFR mutations e.g. para. [0012]-[0014] , it does not provide any mechanistic explanation, data, or guidance for why the combination benefit observed in exon 19 deletion cell lines would extend to these other mutation types.
With respect to the EGFR inhibitor scope, the specification only validates the effect of two EGFR inhibitors (the first generation TKI gefitinib, and the third generation TKI osimertinib). The specification argues (para. [0074]) that these two agents are structurally and mechanistically different from each other (non-covalent vs covalent binding), which provides some basis for extrapolation to tother small molecule TKIs. However, the specification provides no direction or data for monoclonal antibody-based EGFR inhibitors, which act through an entirely different mechanism. The specification does not explain why a combination benefit observed with kinase domain-binding small molecules would extend to antibodies that bind the extracellular domain.
The specification provides working examples 5-7, 9-12 using the following cell lines:
Cell Line
EGFR Mutation
EGFR Inhibitor(s) Tested
Assay Type
HCC827
Exon 19 del
E746-A750
Gefitinib, Osimertinib
In vitro proliferation, gene expression
HCC4006
Exon 19 del
L747-E749
Gefitinib, Osimertinib
In vitro proliferation
NCI-H1975
L858R + T790M
Osimertinib
In vitro proliferation, gene expression, in vivo xenograft
Every working example appears to use either an exon 19 deletion cell line or the NCI-H1975 cell line (L858R + T790M), and every working example uses either gefitinib or osimertinib as the EGFR inhibitor. There are no working examples for:
L858R as a standalone oncogenic driver (i.e., without T790M), exon 18 insertions/deletions exon 20 insertions/deletions, uncommon point mutations (G719X, S768I, L861Q, V765A, T783A, and others listed in claim 3), EGFR gene amplification, kinase domain duplication, or any monoclonal antibody-based EGFR inhibitor (e.g. cetuximab, panitumumab, necitumumab). The absence of any data for monoclonal antibody-based EGFR inhibitors is a notable gap, given the fundamentally different mechanism of action for that class of EGFR inhibitor.
See also 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”).
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 test each untested EGFR mutation type and assess if there is a combination benefit. Each mutation type and each EGFR inhibitor class would need to be independently tested, with no assurance that the combination benefit would be observed. Furthermore, for EGFR mutation types known to be resistant to the tested EGFR inhibitors, the artisan would first need to identify an appropriate EGFR inhibitor that is effective against that mutation type, and then test whether the addition of a CBP/p300 bromodomain inhibitor provides any combination benefit.
Therefore, in view of the factors discussed above, claims 1-8, 10, and 13-15 are rejected as failing to comply with the enablement requirement.
Applicant is invited to amend claim 1 to introduce into claim 1 “wherein the oncogenic alteration is caused by a deletion in exon 19 of the EGFR gene” or some similar language supported by the specification (see e.g. claim 4). Additionally, applicant is invited to narrow the scope of “EGFR inhibitor” in claim 1 to the small molecule EGFR TKI class (e.g. para. [0019]). Extension to monoclonal antibody-based EGFR inhibitors is not considered enabled.
Claim Rejections - 35 USC § 112(b) - New
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 4, 6, and 7 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, claim 4 recites the broad recitation “a deletion in exon 19 of the EGFR gene”, and the claim also recites “preferably a deletion resulting in the deletion of E746-A750 or L747-E749 in the EGFR” which is the narrower statement of the range/limitation. 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.
To overcome the rejection, applicant is invited to introduce the narrower limitation as a new, dependent claim.
Claims 6 and 7 recite the limitation "the resistance alteration" in lines 1-2. There is insufficient antecedent basis for this limitation in the claim. Claim 1 refers to an oncogenic alteration but does not set forth that the NSCLC further comprises a resistance alteration.
To overcome the rejection, applicant is invited to introduce a new claim reciting “The method according claim 1, wherein the NSCLC additionally exhibits a resistance alteration in the EGFR” or some similar language supported by the specification. Claims 5-7 could then depend from that new claim.
Conclusion
Claims 1-8, 10, and 13-15 are rejected.
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 8:30 am - 5:30 pm.
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, 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.
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.
/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621