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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on May 28, 2026 has been entered.
Claim Status
Claims 1, 5-8, 12, 19, 21-25 and 31-35 are under consideration in this office action.
Withdrawn Objections/Rejections
The declaration under 37 CFR 1.132 filed May 14, 2026 is sufficient to overcome the rejection of claim 1 and 19 based upon potential indefinite claim language of CDX-3379 under 35 U.S.C. 112(b).
The rejections of claims 1, 5-8, 12, 19, 21-25 and 31-35 under 35 U.S.C. 112(b) for being indefinite are withdrawn in view of applicant’s amendment.
The rejections of claims 1, 5-8, 12, 19, 21-25, 31, 33, and 35 under 35 U.S.C. 112(a) for failing to meet the written description is withdrawn in view of applicant’s amendment to limit the antibodies to specific antibodies.
Applicant’s arguments with respect to the rejection of claims 1, 5-6, 8, 12, and 31-34 under 35 U.S.C. 103 as being unpatentable over Clarke in view of Aktoudianakis and Huang have been considered but are moot because the new ground of rejection does not rely on Huang et al as applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
New Objections/Rejections
Claim Objections
Claims 19 and 21 are objected to because of the following informalities:
In claim 19, last line, there are errors related to the claim amendment; remove “ r; or” after PD-1 inhibitor and add a period to the end of the claim. Appropriate correction is required.
Claim 21 recites “the level of PD-1 expression” in lines 1-2 and “a level of PD-1 expression” in lines 2-3; consistent use of articles for the noun is required.
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.
Claims 19, 21-25 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2016/059602, published April 21, 2016 (“Clarke”; see IDS from 5/24/2022) in view of US 2019/0270727, published September 5, 2019 (“Aktoudianakis”; see IDS from 5/24/2022).
Claim 19 is directed to a method of treating a subject with head and neck cancer with the anti-HER3 antibody CDX-3379 and a PD-1 inhibitor, the method comprising a step of determining if the subject will benefit from the CDX-3379 and PD-1 inhibitor therapy.
Clarke teaches a method of treating head and neck cancer (pg 34) comprising administering an anti-HER3 antibody and a PD-1 inhibitor (pg 152), as in claim 19. The PD-1 inhibitor is nivolumab or pembrolizumab (pg 86, para 1), as in claim 19. The combination of anti-HER3 antibody with an anti-PD-1 antibody resulted in greater tumor regression in a mouse model of metastatic renal cell carcinoma and greater anti-tumor efficacy (pg 152), as in the patient that can benefit from the treatment of claim 19.
Clarke teaches that activation of HER3 increases PI3K/AKT pathway and that anti-HER3 antibodies inhibit agonist induced HER3 phosphorylation (pg 125). Clarke teaches validation of an anti-HER3 antibody for its use as a diagnostic for determining HER3 expression; the level of HER3 expression can be used to identify patients that may clinically benefit from anti-HER3 antibody therapy (pg 143), as in the limitations of claim 19 directed to the performance of a diagnostic assay on a biological sample to determine if a subject may benefit from anti-HER3 treatment. Clark teaches that the biological sample may have been removed from a human (e.g., a biopsy) (pg 83), and HER3 was detectable in a kidney tumor sample (pg 148), as in the biological sample of instant claim 19 and the tumor biopsy of instant claim 25. Clarke also teaches that the biological sample for diagnostic purposes is serum (pg 83), which is a component of blood, as in claim 35.
The Clarke reference does not teach that the level of PD-1 expression on activated T cells is elevated nor does it teach the anti-HER3 antibody CDX-3379.
Aktoudianakis teaches methods for treating cancer comprised of administering PD-1 inhibitors in combination with the anti-HER3 antibody CDX-3379 [0601], as in instant claim 19. Aktoudianakis teaches that PD-1 is highly expressed on activated T cells, and PD-L1/PD-1 signaling is a primary mechanism of cancer immune evasion [0952]. Inhibition of this pathway can reduce tumor size ([0860], [0868]).
Although Clarke does not specifically disclose wherein the subject can benefit from the treatment if the subject expresses a level of PD-1 on a plurality of activated T cells that when blocked is sufficient to activate tumor-killing activity of the T cells, it would have been obvious to one of ordinary skill in the art that a PD-1 inhibitor in combination with CDX-3379 that is efficacious in decreasing tumor volume, as taught by Clarke and Aktoudianakis, would also be effective to activate tumor-killing activity. The ordinary artisan would include the T cell expression methods of Aktoudianakis in the method of Clarke in order to measure PD-1 expression on T cells and then tailor patient specific treatments using PD-1 inhibitor therapeutics. This is because of the need in cancer cell immunotherapy to develop reliable therapeutics for the treatment of cancer that achieve predictable results.
Claims 1, 5-6, 8, 12, and 31-34 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2016/059602 (“Clarke”) in view of US 2014/0037622, published February 6, 2014 (“Boshoff”; see IDS from 5/24/2022), US 2019/0270727, published September 5, 2019 (“Aktoudianakis”), and Liu et al, published July 2013 (instant PTO-892).
The claims are directed to a method of treating PIK3CA gene modified head and neck cancer by administering an anti-HER3 antibody or fragment thereof and an immune checkpoint modulator.
Clarke teaches a method of treating head and neck cancer (pg 34) comprising administering an anti-HER3 antibody and a PD-1 inhibitor (pg 152), as in instant claim 1. This combination of anti-HER3 antibody with anti-PD-1 antibody resulted in greater tumor regression and greater anti-tumor efficacy (pg 152), demonstrating that the subject can benefit from the combination therapy. The PD-1 inhibitor is nivolumab or pembrolizumab (pg 86, para 1), as in claims 1, 31-32, and 34.
Regarding the limitations of instant claim 8 directed to inhibition of ribosomal protein S6 phosphorylation, Clarke teaches that activation of HER3 increases PI3K/AKT pathway and that anti-HER3 antibodies inhibit agonist induced HER3 phosphorylation (pg 125). Thus, one of ordinary skill will predict that treatment with anti-HER3 antibodies would inhibit HER2 signaling activity, including PI3K and its downstream target S6.
Clarke teaches that the combination therapy of anti-HER3 antibody and checkpoint inhibitor may be used in combination with other chemotherapeutics and/or radiation (pg 63), as in the limitation of instant claim 12.
Clarke does not teach a method of treating a subject with a cancer that expresses PIK3CA gene modifications, as required by instant claim 1.
Boshoff teaches a method of treating head and neck cancer and that head and neck squamous cell carcinoma have genetic alterations, including modified PIK3CA gene [0043], as in instant claim 1. Boshoff teaches a method of treating head and neck cancer that is HPV positive [0005], as in instant claim 5. Boshoff teaches a method for treating head and neck cancer that is a solid tumor or metastatic lesion, as in instant claim 6.
Given that Clarke teaches a method of treating head and neck cancer by administering a combination therapy comprising an anti-HER3 antibody and an immune checkpoint inhibitor and further given that Boshoff teaches species of head and neck squamous cell carcinoma associated with modification in the PIK3CA gene or head and neck cancer related to HPV infection, it would have been obvious to the ordinary artisan to treat the subjects of Boshoff with the treatment method of Clarke. The motivation to do some comes from Boshoff, who teaches that patients with a head and neck cancer who are HPV-positive exhibit alterations in PI3K activity and that these patients are more likely to benefit from treatment with a PI3K inhibitor [0004]. As the anti-HER3 antibody of Clarke decreases PI3K activity, it would have been obvious to the ordinary artisan that the method of Clarke for treatment of head and neck cancer would be applicable to different types of head and neck cancer that are associated with an aberrant upregulation PI3K; applying a known technique to a known disease ready for improvement will yield predictable results (see MPEP 2143).
Clarke in view of Boshoff does not teach the anti-HER3 antibody CDX-3379, as required by instant claim 9.
Aktoudianakis teaches methods for treating cancer comprised of administering PD-1 inhibitors in combination with the anti-HER3 antibody CDX-3379 [0601], as in instant claim 9.
Given that Clarke in view of Boshoff teaches a method of treating head and neck cancer with a combination therapy of anti-HER3 antibody and an immune checkpoint inhibitor and Aktoudianakis teaches the claimed anti-HER3 antibody, it would have bene obvious to one of ordinary skill in the art to use the antibody of Aktoudianakis in place of the anti-HER3 antibody of Clarke. This is because, as stated in MPEP §2144.06, substituting one equivalent element for another known for the same purpose renders an invention obvious and an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious.
The teachings of Clarke in view of Boshoff and Aktoudianakis are discussed above; this combination of references does not teach the method wherein the PIK3CA gene comprises the mutation R115, E542, E545, or H1047, as required by claims 1 and 33.
Liu et al teaches the PIK3CA mutations of R115L, E542K, E545K, and H1047R (pg 764, column 1, para 3), as in the mutations of instant claims 1 and 33. These mutations of PIK3CA were associated with enhanced cell growth and upregulated the PI3K pathway (pg 764, column 1). HNSCC cells lines with these mutations showed increased sensitivity to PI3K pathway inhibition (pg 764, column 2).
Given that Clarke, Boshoff, and Aktoudianakis teach a method of treating head and neck cancer comprising administering CDX-3379 and a PD-1 inhibitor, wherein the cancer expresses a PIK3CA gene modification, and further given that Liu et al teaches mutations in PIK3CA that contribute to the tumorigenicity of head and neck cancer, one of ordinary skill in the art would be able to envision immediately the methods of claims 1 and 33 directed to a PIK3CA gene mutant at R115 or E542. This is because, as stated in MPEP §2144.06, substituting one equivalent element for another known for the same purpose (i.e. the mutant of Liu et al in the modified PIK3CA of Boshoff) renders an invention obvious and an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious.
Claims 1, 5-8, 12 and 31-32 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2016/059602 (“Clarke”) in view of US 2014/0037622 (“Boshoff”), US 2019/0270727 (“Aktoudianakis”), and Liu et al, published July 2013, as applied to claims 1, 5-6, 8, 12, and 31-32 above, and further in view of Haratani et al, published December 3, 2019 (see PTO-892 from 9/22/25).
The teachings of Clarke in view of Boshoff and Aktoudianakis are discussed above; this combination of references does not teach a method of treating cancer wherein the head and neck cancer is resistant to a PD-1 treatment in the absence of the anti-HER3 antibody, as required by instant claim 7.
Haratani et al teaches that combination therapy with PD-1 inhibitor and anti-HER3 antibody-drug conjugate significantly enhances the anti-tumor immunity of PD-1 blockade in a syngeneic mouse tumor model that is refractory to anti-PD-1 therapy (abstract).
Given that Clarke in view of Boshoff teaches that anti-HER3 antibody and PD-1 inhibitor combination therapy results in greater tumor regression in a mouse model of cancer and greater anti-tumor efficacy in subjects with a cancer expressing a PIK3CA gene modification, and further given Haratani et al teaches improved anti-tumor efficacy of combination therapy in an animal that is refractory to anti-PD-1 therapy, it would have been obvious to one of ordinary skill in the art to apply the treatment method of Clarke in view of Boshoff to a patient who is non-responsive to anti-PD-1 monotherapy. One would do so and have a reasonable expectation of successfully treating this patient, as the combination therapy demonstrates improved anti-tumor efficacy over anti-PD-1 monotherapy. Such would amount to the combining of prior art elements according to known methods to achieve predictable outcomes, see MPEP 2143.I.A.
Response to Arguments
Applicant's arguments filed May 28, 2026 have been fully considered.
With respect to the rejection of the claims under 35 U.S.C. 103, applicant argues that the administration of CDX-3379 with an anti-PD-1 therapy is associated with unexpectedly good synergistic effects, compared to monotherapy (remarks, 6). Although it is clear that the combination treatment is better than each treatment alone, it is not clear that the combination treatment is associated with unexpected synergy. Applicant’s assertion that the unique binding activity of the CDX-3379 antibody distinguishes it from other anti-HER3 antibodies in the art and those in Clarke et al (pg 6, 8). When the results are considered in view of Clarke et al, the examiner finds that the claimed method is not associated with unexpectedly superior results. Clarke et al teaches a method of treating cancer using anti-HER3 antibodies in combination with an anti-PD-antibody in a syngeneic xenograft model of renal cell carcinoma (pg 14). In mice administered anti-HER3 and anti-PD-1 antibodies, 7/10 mice were tumor free at 30 days (Figure 63), whereas in mice administered anti-HER3 antibody alone, 2/10 were tumor free (Figure 61). In mice administered anti-PD-1 alone, 1/10 were tumor free (Figure 59), and in mice treated with vehicle or IgG alone, 0/10 were tumor free at 30 days (Figures 56-57). Although the anti-HER3 antibodies in Clarke et al are structurally different than CDX-3379, they are functionally equivalent, and it would have been obvious to the ordinary artisan to substitute the antibody of Clarke et al with CDX-3379 and the results were reasonably predictable. In order to overcome this rejection, applicant must show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) (see MPEP 716.02(a)I).
Applicant’s arguments related to Boshoff, Haratani, and Aktoudianakis (pg 8-9) have been considered but they do not show how the combined teachings and the knowledge/skills contained therein cannto render the rejected claims obvious. Because Clarke et al teaches that the combination of anti-HER3 inhibitor antibodies and PD-1 antibodies is superior to monotherapy, the rejections of the claims for being obvious over Clarke et al and other cited references are maintained.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNIFER BENAVIDES whose telephone number is (571)272-0545. The examiner can normally be reached M-F 9AM-5PM (EST).
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, Jeffrey Stucker can be reached at (571)272-0911. 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.
Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/Examiner, Art Unit 1675
Prosecution Insights