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 .
Claim Status
Applicant’s amendment filed February 9, 2024 has been received and entered.
Claims 3, 6, 10, 14, 16, and 20 have been amended.
Claims 2, 4, 7-9, 11, 13, 17, 21, and 30 have been canceled.
Claims 1, 3, 5-6, 10, 12, 14-16, 18-20, and 22-29 are pending and under consideration.
Priority
This application was filed October 27, 2023.
Information Disclosure Statements
The information disclosure statements (IDSs) submitted on March 6, 2024 and May 5, 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claims 1, 10, and 14 are objected to for the following informalities:
Claims 1 and 14 (part 2) recite “determining the expression level of epidermal growth factor receptor (EGFR) on the biological material…”, however, should read “determining the expression level of epidermal growth factor receptor (EGFR) in the biological material…”
Claim 10 (line 1) recites “immune checkpoint inhibitor”, but to be consistent with the other claims, the claim should read “ICI”.
Claim 10 - pembrolizumab and nivolumab are both listed twice.
Appropriate correction is required.
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.
Claims 5 and 14 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 5 recites “The method of claim 1, wherein in step (4) no therapeutic benefit is predicted if at least 5% of the cells of the biological sample from the patient express EGFR”. There is no antecedent basis for “the cells” in claim 1.
Claim 14 is drawn to a method of treatment of a cancer patient with an ICI, including the method of claim 1, the method comprising the steps of:
Providing a biological sample from the patient;
Determining the expression level of epidermal growth factor receptor (EGFR) on the biological material to obtain CEGFRPat;
Comparing CEGFRPat with the expression level of EGFR in a reference biological sample CEGFRRef;
Refraining from administering the ICI to the patient if CEGFRPat > CEGFRRef;
or
Administering the ICI to the patient if CEGFRPat ≤ CEGFRRef.
It is unclear how the method of 14 (drawn to treating cancer) also includes the method of claim 1 (drawn to predicting a patient’s benefit from therapy with an ICI inhibitor). Specifically, claim 14 fails to define how claim 1 falls under a treatment for cancer, as steps 1-3 are also recited in claim 1.
Appropriate correction is required.Claim rejections - 35 USC § 101
35 U.S.C. § 101 reads:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
For each rejection below, dependent claims are rejected similarly as not remedying the rejection, unless otherwise noted.
Judicial Exceptions to 101 Patentability
Claims 1, 3, 5-6, 10, and 12 are rejected under 35 U.S.C. § 101 because the claimed inventions are not directed to patent eligible subject matter.
The claimed invention is directed to a correlation of predicting the benefit of immune checkpoint inhibitor therapy without significantly more. The claim(s) recite(s) a correlation which is deemed a law of nature. This judicial exception is not integrated into a practical application because the claims only recite the natural correlation and steps of comparison and do not integrate the judicial exception. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the steps are considered general and routine knowledge in the prior art.
The claims are drawn to quantifying EGFR expression in a patient tissue samples, comparing, determining values, calculating and comparing results.
Dependent claims set forth further limitations for the type of sample tissue and type of patient. These dependent claims do not provide anything more than the judicial exception because the claims merely limit types that are naturally occurring and are in the general population.
According to the 2019 Patent Eligibility Guidance an initial two step analysis is required for determining statutory eligibility.
MPEP 2106 organizes judicial exception analysis into Steps 1, 2A (1st & 2nd prongs) and 2B as follows:
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter?
YES: The claims are directed to a process.
Step 2A, Prong one: Do the claims recite a judicially recognized exception, i.e. a law of nature, a natural phenomenon, or an abstract idea?
YES: The claims recite a law of nature and an abstract idea.
The correlation of a therapeutic benefit and cellular expression of EGFR is considered a natural correlation.
The calculation of the difference between two values is considered an abstract idea. This is considered a mental process.
Step 2A, Prong two: Does the claim recite additional elements that integrate the judicial exception into a practical application?
NO: The steps require only routine and conventional steps and does not integrate the judicial exception to a practical application.
Step 2B: Does the claim recite additional elements that are significantly more than the judicial exceptions?
NO: Amaral et al. (2023; cited IDS 5/05/2025) teaches methods for predicting the benefit of immune checkpoint inhibitor therapy in melanoma patients comprising measuring EGFR expression in primary tumor and metastatic tissue by immunohistochemistry. Amaral teaches patients with high EGFR expression in metastatic tissue had a significantly higher relapse rate than those with low EGFR expression, indicating that EGFR can be used as a prognostic biomarker to stratify patients for adjuvant ICI therapy [Results, Conclusions].
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 12, 14-16, and 24-27 are rejected under 35 U.S.C. 103 as being unpatentable over Amaral et al. (J Clin Oncol, 2023; 41(16suppl):e21566; cited IDS 5/05/2025) (“Amaral”).
The instant claims are drawn to a method of predicting benefit from therapy with an immune checkpoint inhibitor (ICI) in a patient having melanoma, comprising determining the expression level of EGFR in a biological sample obtained from the patient, wherein the biological sample is primary or metastatic melanoma tissue, and comparing it to the EGFR expression level in a reference sample, wherein if the EGFR expression level is greater than the expression level in the reference sample the patient will not benefit from treatment with an ICI. An expression level equal or less than the expression level in the reference sample indicates the patient should be treated with an ICI.
Amaral teaches methods for predicting the benefit of immune checkpoint inhibitor therapy in resected stage III/IV melanoma patients [Background] (instant claims 1 (partial), 12, 15-16, 25-26). Amaral measured epidermal growth factor receptor (EGFR) expression in primary tumor and metastatic tissue from patients using immunohistochemistry, including patients receiving adjuvant ICI therapy [Methods] (instant claims 1, 14, 27 (partial), 3, 24). Amaral found that EGFR expression in therapy naive metastatic tissue is positively associated with relapse in patients receiving adjuvant ICI. Therefore, EGFR can be used as a prognostic biomarker that can easily be assessed by immunohistochemistry, allowing the stratification of patients for adjuvant ICI therapy according to their risk of relapse [Conclusions] (instant claims 1, 14, 27 (partial)).
The instant specification discloses the reference sample is a biological sample with average or normal EGFR expression, either from a healthy tissue of the patient or another individual [0021-0022].
The teachings of Amaral differ from the present invention in that EGFR expression can be used as a biomarker to predict the benefit of ICI therapy in metastatic melanoma patients, the EGFR expression levels are not explicitly taught as being compared to a reference sample. Given that Amaral teaches that melanoma patients with low EGFR expression had a significantly lower relapse rate after ICI therapy than patients with high EGFR expression, the skilled artisan would have a reasonable expectation of success in comparing a patient sample with the EGFR expression level of a reference sample (i.e. a sample from a healthy individual) and determining that the patient was at risk for relapse if their EGFR expression levels were higher than the reference sample before prescribing an ICI therapy. A person having ordinary skill in the art would be motivated to compare the EGFR expression level in a patient sample to the expression level in a reference sample before prescribing an ICI therapy because melanoma patients with low EGFR expression had significantly lower levels of relapse after receiving ICI therapy. Therefore, melanoma patients with low EGFR expression profiles are candidates for adjuvant ICI therapy as evidenced by Amaral. As such, the invention as a whole was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention.
Claims 6, 10, 19-20, and 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over Amaral et al. (J Clin Oncol, 2023; 41(16suppl):e21566; cited IDS 5/05/2025) (“Amaral”) as applied to claims 1, 3, 12, 14-16, and 24-27 above, and in further view of Lee et al. (Ann Dermatol, 2021; 33(5):432-439) (“Lee”).
The instant claims are drawn to a method of predicting benefit from therapy with an immune checkpoint inhibitor (ICI) in a patient having melanoma, comprising determining the expression level of EGFR in a biological sample obtained from the patient, wherein the biological sample is primary or metastatic melanoma tissue, and comparing it to the EGFR expression level in a reference sample, wherein if the EGFR expression level is greater than the expression level in the reference sample the patient will not benefit from treatment with an ICI. An expression level equal or less than the expression level in the reference sample indicates the patient should be treated with an ICI, wherein the ICI is an anti-PD-1 antibody such as pembrolizumab or nivolumab, or an anti-CTLA-4 antibody such as ipilimumab.
The teachings of Amaral are set forth above.
Amaral does not teach any specific ICI therapy.
Lee teaches that the current first-line standard treatments for metastatic melanoma are PD-1 blockade (nivolumab, pembrolizumab) with or without CTLA-4 blockade (ipilimumab) [pg. 433, col. 1, last par.] (instant claims 6, 10, 19-20, and 22-23).
The teachings of Amaral differ from the present invention in that even though EGFR expression for determining if a melanoma patients is a candidate for ICI therapy is taught, the specific type(s) of ICI therapy for treating melanoma are not. Given that Lee teaches that pembrolizumab or nivolumab with or without ipilimumab is the first line treatment for metastatic melanoma, one of ordinary skill in the art would have a reasonable expectation of success in administering pembrolizumab or nivolumab with or without ipilimumab as an ICI therapy to patients whose samples had EGFR expression levels lower than the EGFR reference level because Amaral teaches low EGFR expression is correlated with lower risk of relapse after ICI therapy, supporting its use in a treatment regimen. Therefore, the instant invention was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention in view of the combined references.
Claims 5 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Amaral et al. (J Clin Oncol, 2023; 41(16suppl):e21566; cited IDS 5/05/2025) (“Amaral”) as applied to claims 1, 3, 12, 14-16, and 24-27 above, and in further view of de Wit et al. (J Invest Dermatol, 1992; 99(2):168-173) (“de Wit”).
The instant claims are drawn to a method of predicting benefit from therapy with an immune checkpoint inhibitor (ICI) in a patient having melanoma, comprising determining the expression level of EGFR in a biological sample obtained from the patient, wherein the biological sample is primary or metastatic melanoma tissue, and comparing it to the EGFR expression level in a reference sample, wherein if the EGFR expression level is greater than the expression level in the reference sample the patient will not benefit from treatment with an ICI, wherein no therapeutic benefit is predicted if at least 5% of the cells of the biological sample from the patient express EGFR, wherein no ICI is administered if at last 5% of the cells from the patient express EGFR.
The teachings of Amaral are set forth above.
Although Amaral teaches high and low EGFR expression levels measured via IHC, Amaral is silent regarding what values represent high or low EGFR expression.
de Wit teaches immunohistochemical methods for measuring EGFR expression in human melanocytic lesions. de Wit compared EGFR expression in six human melanoma cell lines and found differential EGFR expression in various stages of tumor progression, ranging from 19% positive (common nevocellular nevi) to 91% positive (melanoma metastasis) [Abstract]. Lesions were regarded EGFR positive if 5% or more of the melanocytic cells in the lesion stained [see Score, pg. 169] (instant claims 5, 18).
It would have been obvious to one of ordinary skill in the art to combine the methods of Amaral with those of de Wit to provide a threshold value for positive EGFR expression because de Wit teaches melanoma cells are EGFR positive if at least 5% of cancer cells stain positive. Therefore one would have a reasonable expectation of success in treating melanoma with an ICI by selecting patients with EGFR expression lower than 5%, because those patients are considered EGFR-negative and therefore more likely to respond to ICI therapy as evidenced by Amaral. Therefore, the instant invention was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention in view of the combined references.
Claims 28-29 are rejected under 35 U.S.C. 103 as being unpatentable over Amaral et al. (J Clin Oncol, 2023; 41(16suppl):e21566; cited IDS 5/05/2025) (“Amaral”) as applied to claims 1, 3, 12, 14-16, and 24-27 above, and in further view of Seth et al. (J Clin Oncol, 2023; 41(30):1-30) (“Seth”).
The instant claims are drawn to a method of predicting benefit from therapy with an immune checkpoint inhibitor (ICI) in a patient having melanoma, comprising determining the expression level of EGFR in a biological sample obtained from the patient, wherein the biological sample is primary or metastatic melanoma tissue, and comparing it to the EGFR expression level in a reference sample, wherein if the EGFR expression level is greater than the expression level in the reference sample the patient will not benefit from treatment with an ICI. An expression level equal or less than the expression level in the reference sample indicates the patient should be treated with an ICI, wherein an EGFR expression level greater than the reference sample indicates the patient is treated with an alternative therapy such as a small molecule inhibitor.
The teachings of Amaral are set forth above.
Amaral teaches methods for predicting response to ICI therapy by measuring EGFR expression in melanoma samples, but does not provide alternate therapies for patients that are not candidates for ICI therapy.
Seth teaches after progression on first-line anti-PD-1 based therapy, patients with BRAF mutant (V600) unresectable and/or metastatic cutaneous melanoma may be offered combination BRAF/MEK inhibitor therapy [see Recommendation 3.4, pg. 4] (instant claims 28-29).
Given that Amaral teaches high EGFR expression in melanoma patients predicts risk of relapse after treatment with an ICI, and therefore makes a patient ineligible for treatment with an ICI, it would have been obvious to one of ordinary skill to select a BRAF/MEK inhibitor as the course of treatment because Seth teaches BRAF/MEK small molecule inhibitors are the second line of therapy for metastatic melanoma patients that have progressed on a first line anti-PD-1 therapy. Therefore, the instant invention was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention in view of the combined references.
Conclusion
No claim is allowed.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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