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 response to applicant’s filling dated November 3, 2023. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The present application claims benefit under 35 U.S.C. 119(e) to provisional application US 63422257, filed 11/03/2022.
Status of Claims
Claims 1-20 are pending and are being examined on the merits.
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 1-20 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 a head and neck squamous cell carcinoma cancer in a subject in need thereof comprising an effective amount of cetuximab and erdafitinib, does not reasonably provide enablement for treating all types of cancer by administering any FGFR inhibitor in combination with any type of EGFR 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 practice the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the Invention Claims 1-6 and 9-18 are drawn to a method of treating a generic form of cancer. However, because each cancer has a mutually exclusive etiology and pathophysiology and is drawn to a different patient population, there is not a sufficient degree of predictability in the prior art or evidence in the specification as filed to suggest that such a treatment directed to head and neck squamous cell carcinoma would be applicable to all other forms of cancer and the specification is not enabling for all forms of cancer (U1, CRI Staff. “Exploring the Different Types of Cancer and Treatment Options” Immune to Cancer: The CRI Blog, (2023) pp. 1-2).
Claims 7, 8, 19, and 20 which are drawn to a method of treating a form of head and neck cancer resistant to an EGFR inhibitor with a combination of an EGFR inhibitor and FGFR inhibitor. However, given the different mechanisms of action, pharmaceutical properties, and combination compatibility of different EGFR and FGFR inhibitors, there is not a sufficient degree of predictability in the prior art or evidence in the specification as filed to suggest that generic EGFR and FGFR inhibitors are both safe to use in combination and are effective against head and neck cancers resistant to an EGFR inhibitor (V1, ABOUREHAB, MAS et al. “Globally approved EGFR inhibitors: insights into their syntheses, target kinases, biological activities, receptor interactions, and metabolism” Molecules, Vol 26, No. 21, (2021) pp. 1-5; W1 KATOH, M et al. “FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions” Nature Reviews Clinical Oncology, Vol 24, No.4, (2024) pp. 312-316; X1, LAPOINT, L. “What is combination drug therapy” Tufts Now, (2022) pp. 2-4).
Breath of the Claims: The claims are broad in that they recite a method where any cancer, wherein the cancer is resistant to any epidermal growth factor inhibitor, is treated by any combination of an EGFR inhibitor and a FGFR inhibitor. The heterogeneous nature of cancer etiology and pathophysiology as well as the different mechanisms of action within EGFR and FGFR inhibitors is greatly exacerbated by the breath of the claims (U1, CRI Staff. “Exploring the Different Types of Cancer and Treatment Options” Immune to Cancer: The CRI Blog, (2023) pp. 1-2). Although some dependent claims recite aspects (particular cancers, EGFR inhibitors, and FGFR inhibitors) which in isolation may be enabled, they incorporate aspects from the independent claim which make the dependent claim overly broad (e.g. claim 4 recites a combination utilizing the EGFR inhibitor cetuximab in combination with a FGFR inhibitor applied to a cancer which is resistant to EGFR inhibitors).
Guidance of the Specification and Existence of Working Examples: The specification describes administering the EGFR inhibitor cetuximab, the FGFR inhibitor erdafitinib, and a combination of both inhibitors to treat humanized mice with head and neck squamous cell carcinoma patient-derived xenografts resistant to an EGFR inhibitor and the change in tumor volume across all samples over the 32-day trial.
This specification envisions that administering an EGFR inhibitor, selected from cetuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab, gefitinib, erlotinib, brigatinib, lapatinib, and osimertinib, in combination with a FGFR inhibitor, selected from erdafitinib, pemigatinib, infigratinib, derazantinib, and futibatinib, to treat a generic form of cancer, wherein the combination of any one of the EGFR inhibitors in combination with any one of the FGFR inhibitors would be capable of slowing tumor progression and inducing remission in a generic form of cancer.
However, no working examples of combinations of EGFR and FGFR inhibitors for treating cancers have been taught by the specification, besides the embodiment of a combination of cetuximab and erdafitinib for treating head and neck squamous cell carcinoma. Therefore, the applicant is not enabled for alternative combinations of inhibitors or therapeutic applications to cancer types beyond head and neck squamous cell carcinoma.
Predictability and State of the Art: The state of the art at the time of invention demonstrates that there are major differences between different drug modes of action (V1, ABOUREHAB, MAS et al. “Globally approved EGFR inhibitors: insights into their syntheses, target kinases, biological activities, receptor interactions, and metabolism” Molecules, Vol 26, No. 21, (2021) pp. 1-5; W1 KATOH, M et al. “FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions” Nature Reviews Clinical Oncology, Vol 24, No.4, (2024) pp. 312-316), the efficacy and safety of different pharmaceuticals when used in combination versus their monotherapy usage (X1, LAPOINT, L. “What is combination drug therapy” Tufts Now, (2022) pp. 2-4), and the different variants of cancer responses different types of cancer may have to different drugs (U1, CRI Staff. “Exploring the Different Types of Cancer and Treatment Options” Immune to Cancer: The CRI Blog, (2023) 1-2). Although, it was known that certain combinations of FGFR and EGFR inhibitors were effective against certain cancer varieties, it is not predictable that any given combination of EGFR and FGFR inhibitors will act as a possible treatment for any cancer which is resistant to an EGFR inhibitor (U2, MICHMERHUIZEN, NL et al. “Small molecule profiling to define synergistic EGFR inhibitor combinations in head and neck squamous cell carcinoma” Head & Neck, Vol 44, No. 5, (2022) 1192-1193).
Amount of Experimentation Necessary: The amount of experimentation necessary to carry out the claimed invention is high, as the skilled artisan could not rely upon the prior art or instant specification to teach the methods of using any listed FGFR inhibitor with any combination of the listed EGFR inhibitors for the treatment of any generalized form of cancer in vivo. In order to carry out the claimed invention, one of ordinary skill in the art must first determine the efficacy of every FGFR inhibitor and EGFR inhibitor combination against every cancer type resistant to an EGFR inhibitor.
In view of the nature of the invention, the breath of the claims, the lack of guidance in the specifications, the unpredictability in the art, and the undue amount of additional experimentation necessary for a skilled artisan, claims are no considered to be fully enabled by the instant specifications.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 3, 5, 7, and 8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Michmerhuizen et al. (U2, MICHMERHUIZEN, NL et al. “Small molecule profiling to define synergistic EGFR inhibitor combinations in head and neck squamous cell carcinoma” Head & Neck, Vol 44, No. 5, (27 February 2022): 1192-1202).
Michmerhuizen et al. teaches combinations of EGFR and FGFR inhibitor are effective against head and neck squamous cell carcinoma models resistant to EGFR inhibitor monotherapies (See e.g. page 1202, paragraph 2, which reads on claims 1, 3, 5, 7, and 8). Michmerhuizen performed a high throughput drug screen using a Resazurin Assay a small molecule inhibitor library and the EGFR inhibitor gefitinib as monotherapies and combinations against EGFR inhibitor resistant head and neck squamous cell carcinoma cell lines (See e.g. page 1194, paragraph 2). Michmerhuizen found especially high synergy between gefitinib and FGFR inhibitors (See e.g. page 1199, paragraph 3, which reads on claims 1, 3, 5, 7, and 8). Michmerhuizen then conducted a downstream validation experiment where combinations of gefitinib and the FGFR inhibitor BGJ398 (infigratinib) were used to treat mouse xenografts of the EGFR inhibitor resistant head and neck squamous cell carcinoma cell line UM-SCC-108 (See e.g. page 1195, paragraph 8, which reads on claims 1, 3, 5, 7, and 8). Michmerhuizen found that the EGFR and FGFR inhibitor combinations led to an improved efficiency against the vehicle and therapeutics as monotherapies and led to a decrease in tumor volume in animal models (See e.g. page 1201, figure 5(B), which reads on claims 1, 3, 5, 7, and 8).
Regarding claims 1, 3, 5, 7, and 8, Michmerhuizen teaches a method of treating a head and neck squamous cell carcinoma resistant to an EGFR inhibitor with a therapeutically effective amount of the FGFR inhibitor infigratinib in combination with a therapeutically effective amount of the EGFR inhibitor gefitinib.
Claims 1-3, 5-6, 9-10, 12-15, 17, and 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Haura et al. (V2, HAURA, EB et al. “Erdafitinib overcomes FGFR3-TACC3-mediated resistance to Osimertinib” Journal of Thoracic Oncology, Vol 15, No. 9, (September 2020), pp. e154-e156.)
Haura et al. teaches of a 39-year-old man diagnosed with metastatic adenocarcinoma who developed resistance to the EGFR inhibitor osimertinib as determined by a continued cancer progression in the left lung despite an osimertinib regiment (See e.g. page 154, paragraph 2). Haura found that when given 8 mg of the FGFR inhibitor erdafitinib in combination with continuing the 80 mg osimertinib regiment, that the patient the tumor partially receded as determined by a computed tomography scan (See e.g. page 154, paragraph 2, which reads on claims 1-3, 5-6, 9-10, 12-15, 17, and 18).
Regarding claims 1-3, 5, and 6, Haura teaches a method of treating a cancer resistant to an EGFR inhibitor in a human with a therapeutically effective amount of the FGFR inhibitor erdafitinib in combination with a therapeutically effective amount of the EGFR inhibitor osimertinib.
Regarding claims 9, 10, and 12, Haura teaches a method where a cancer is determined to be resistant to treatment by an EGFR inhibitor in a human patient, then administering to the subject a therapeutically effective amount of the FGFR inhibitor erdafitinib in combination with a therapeutically effective amount of an EGFR inhibitor.
Regarding claims 13-15, 17, and 18, Haura teaches a method where the human subject was previously administered the EGFR inhibitor osimertinib, the cancer developed resistance to the EGFR inhibitor, and a therapeutic amount of the FGFR inhibitor erdafitinib.
Claim Rejections - 35 USC § 103
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 non-obviousness.
Claims 1-5, 7, 8, 13-17, 19, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Dunn et al. (W2, DUNN, L et al. “A phase I/Ib study of levantinib and cetuximab in patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC)” Journal of Clinical Oncology, Vol 38, No. 15 supplement, (25 May 2020) pp. 1-2), in view of Bernat-Peguera et al. (X2, BERNAT-PEGUERA, A. et al. “FGFR inhibition overcomes resistance to EGFR-targeted therapy in epithelial-like cutaneous carcinoma” Clinical Cancer Research, Vol 27, No. 5, (1 March 2021) pp. 1-2).
Dunn et al. teaches of a phase 1/1b clinical trial for recurrent/metastatic head and neck squamous cell carcinoma patients where patients who had a limited response to the EGRF inhibitor cetuximab were given the FGFR inhibitor Lenvatinib (See e.g. page 1, abstract). Dunn then found that the pharmaceutical combination of both inhibitors produced improved efficacy justifying advancement in clinical trials (See e.g. page 1, abstract).
While Dunn teaches a method of treating a cancer with a combination of cetuximab and a FGFR inhibitor, it does not teach that such a treatment would be effective against EGFR inhibitor resistant cancers.
However, Bernat-Peguera et al. conducted induced resistance to an EGFR inhibitor in squamous cell carcinomas through a previous regiment of the EGFR inhibitor gefitinib (See e.g. page 1, abstract). They found that the combination of both gefitinib EGRF inhibitor and a FGRF inhibitor were able to treat squamous cell carcinoma with an intrinsic or acquired resistance to EGFR inhibitors (See e.g. page 1 abstract, which reads on claims 1-3, 5, 7, 8, 13-15, 17, 19-20). Bernat-Peguera further suggested that their results may be applicable to EGFR and FGFR inhibitor combinations in general for the treatment of EGFR inhibitor resistance in squamous cell carcinoma (See e.g. page 1, abstract, which reads on claims 1-3, 5, 7, 8, 13-15, 17, 19-20).
A person of ordinary skill in the art before the effective filling date would have had a reasonable expectation of success in using the EGFR inhibitor cetuximab with an FGFR inhibitor to treat EGFR inhibitor resistant head and neck squamous cell carcinoma because Dunn et al. teaches a clinical study where cetuximab in combination with an FGFR inhibitor were able to treat patients with head and neck squamous cell carcinoma exhibiting a limited response to cetuximab monotherapy and Bernat-Peguera found that FGFR inhibitors in combination with EGFR inhibitors can help overcome EGFR inhibitor resistance in squamous cell carcinomas mouse models. The skilled artisan would have been motivated to use the cetuximab and FGFR combination to treat EGFR resistant head and neck squamous cell carcinoma cancers because of a suggestion in Bernat-Peguera which identifies EGFR and FGFR inhibitor combinations being translationally relevant and opening new avenues to treat squamous cell carcinomas resistant to EGFR monotherapies. This suggestion would have led one of ordinary skill in the art to make the obvious modification of therapeutic protocol and cancer target from Dunn et al. however to act on cancer variants resistant to EGFR inhibitor monotherapies.
Claims 1-5, 7, 8, 9-11, 13-17, 19, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Dunn et al. (W2, DUNN, L et al. “A phase I/Ib study of levantinib and cetuximab in patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC)” Journal of Clinical Oncology, Vol 38, No. 15 supplement, (25 May 2020) pp. 1-2) in view of Bernat-Peguera et al. (X2, BERNAT-PEGUERA, A. et al. “FGFR inhibition overcomes resistance to EGFR-targeted therapy in epithelial-like cutaneous carcinoma” Clinical Cancer Research, Vol 27, No. 5, (1 March 2021) pp. 1-2) and Collins (U3, COLLINS, S. “When cancer treatments stop working: is it the end of the line” CURE. (3 November 2021) pp. 3-4).
Dunn et al. teaches a method of treating recurrent/metastatic head and neck squamous cell carcinoma cancer in human patients with a therapeutically effective amount of an FGFR inhibitor in combination with a therapeutically effective amount of the EGFR inhibitor cetuximab (See e.g. page 1, abstract).
Dunn fails to teach a method where the cancer is first determined to be resistant to an EGFR inhibitor.
Bernat-Peguera et al. teaches that the combination of an FGFR inhibitor with an EGFR regiment, is effective at overcoming EGFR resistance (See e.g. page 1, abstract, which reads on claims 1-3, 5, 7, 8, 13-15, 17, 19-20).
Furthermore, Collins teaches a medical practice where a doctor determines if a cancer becomes resistant to a therapy the patient needs to switch or add new medications (See e.g. pages 3-4).
It it would have been obvious to one of ordinary skill in the art before the effective filing date to determine if a cancer is resistant to EGFR inhibitor monotherapies and if so to switch or add new medications following the general practice recited by Collins. Given that Bernat-Peguera showed that the addition of FGFR inhibitors has been shown to overcome EGFR inhibitor resistance and their suggestion that such a method could be translationally applicable in practice for treating EGFR inhibitor resistance in Head and Neck Squamous Cell Carcinoma, it would be obvious for one to add FGFR inhibitors a regiment with the EGFR inhibitor cetuximab following Dunn et al.
Conclusion
No claims are allowable.
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/AARON RAFANAN ULLMAN/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628