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 .
1. The Amendment filed July 18, 2025 in response to the Office Action of April 18, 2025, is acknowledged and has been entered. Claims 1, 2, 11, 14, 32, 35, 36, 84, 87, 89-91, 95-98 are now pending and being examined. Claims 1, 2, and 95 are amended. Claim 98 is new. Claims are being examined as drawn to the species of:
A. HPV expressing p16, Ki-67, Cyclin D1, p53, ProEx C, E6, and E7 (claims 1 and 2 were previously amended to recite all the proteins);
B. (a) method further requiring the tumor to express PD-L1 (claims 14 and 89); and
C. (a) method further requiring administering an additional anti-cancer agent (claims 35, 36, 90, 91, 95).
D. The elected species of (a) subject population received one or more anti-cancer agents prior to the administration of the nivolumab (claims 81-83, 92-94) has been canceled by cancelation of the claims.
Maintained Rejections
(amendments addressed)
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.
2. Claim(s) 1, 2, 11, 14, 87, and 89 remain rejected under 35 U.S.C. 103 as being unpatentable over NCT02105636 (ClinicalTrials.gov archive, History of Changes, published April 4, 2014); in view of Pai (Oral Oncology, 2013, 49:723-725); Lyford-Pike et al (Cancer Research, 2012, 73:1733-1741); and Seiwert et al (ASCO 2014 annual meeting, May 30-June 3, presentation slides: “A Phase 1b Study of Pembrolizumab (MK-3475) in Patients with HPV-negative and HPV-positive Head & Neck Cancer”); US Patent 10,081,681, Korman et al, claiming priority to September 2013; Best et al (Otolaryngol Clin North Am, 2012, 45:807-822, NIH Public Access Manuscript); Conesa-Zamora et al (American Journal of Pathology, 2009, 132:378-390); Wiest et al (Oncogene, 2002, 21:1510-1517); Pillai et al (Journal of Surgical Oncology, 1999, 71:10-15); Mills et al (American Journal of Surgical Pathology, 2012, 36:1158-1164); US Patent Application Publication 2016/0304607, Sadineni et al, claiming priority to April 2015; Bai et al (Clinical Pharmacokinetics, 2012, 51:119-135); Wang et al (Chapter 9 in “ADME and Translational Pharmakokinetics/Pharmacodynamics of Therapeutic Proteins: Applications in Drug Discovery and Development”, First Edition edited by Honghui Zhou and Frank-Peter Theil; Published 2016 by John Wiley & Sons, Inc.); and Chen et al (Head and Neck Pathology, 2012, 6:422-429).
NCT02105636 teaches clinical treatment of head and neck cancer squamous cell carcinoma (HNSCC or SCCHN) patients with 3 mg/kg of nivolumab every 2 weeks (Arms and Interventions), wherein the patients are histologically confirmed to have SCCHN, wherein the patients are previously treated and metastatic or recurrent after treatment with platinum-based therapy, indicating the previously received platinum-based therapy was not effective (Eligibility).
NCT02105636 does not teach:
The patient has HPV+ and PD-L1+ HNSCC (claims 1, 2, 14, 89);
The HPV+ HNSCC expresses p16, Ki-67, Cyclin D1, p53, ProEx C, E6 and E7 (claims 1, 2);
The HNSCC is subtype HPV-16 (claims 1, 2, 11, 87).
Administering nivolumab at 240 mg (claims 1, 2);
The HNSCC tumor has more than 70% of tumor cells showing strong and diffuse nuclear and cytoplasmic staining by an immunohistochemistry against p16 (claims 1, 2);
Pai teaches HPV is recognized as the causative agent in a growing subset of head and neck cancers including HNSCC. Pai teaches that all HPV-infected cells express viral proteins E6 and E7 as antigens that are highly immunogenic to the patients, however, HPV escapes this primed immune response through the PD-1/PD-L1 immunosuppressive pathway. Pai teaches they measured both PD-1 and PD-L1 expression in HPV+ HNSCCs and determined that over 70% of activated CD8+ TILs in HPV+ HNSCC expressed high levels of PD-1 receptor as compared to 35% of CD8+ T cells isolated from benign, chronically inflamed tonsils (p. 723, col. 1-2). Pai teaches they determined up to 70% of HPV_ HNSCC expressed membranous PD-L1 which was juxtaposed to activated CD3+CD8+ T cells (Figure 1A). Pai determined that CD8+ TILS present in HPV+ HNSCCs are activated and secreting IFNɣ, which is then driving the expression of PD-L1 on the tumors. Functional assays demonstrated that the CD8+PD-1+TILs isolated from the PD-L1+ tumors are functionally anergic and suppressed in their capacity to produce additional effector cytokines such as IFNɣ (Figure. 2). Pai concludes that based on these findings, the PD-1:PD-L1 pathway become induced during the development of HPV+HNSCC as an adaptive immune resistance mechanism in response to local IFNɣ secretion by activated tumor specific T cells, which protects the cancer cells from immune elimination (p. 723, col; 2). Pai teaches that the PD-1:PD-L1 pathway plays a role in both persistence of HPV infection (through expression of PD-L1 in the tonsillar crypt epithelium- the site of initial infection) as well as resistance to immune elimination during malignant progression (p. 723, col. 2 to p. 724, col. 1). Pai teaches the known strategy for blockade of the PD-1:PD-L1 checkpoint with monoclonal antibodies to reverse the anergic state of tumor-specific T cells and thereby enhancing antitumor immunity. Known successful blockade of immune checkpoints include: 1) anti-CTLA-4 antibody ipilimumab that has demonstrated survival benefit in advanced metastatic melanoma patients; and 2) anti-PD-1 antibody nivolumab (MDX-1106) that demonstrated clinical activity in a variety of solid tumors including metastatic melanoma, colorectal cancer, NSCLC, and renal cell carcinoma. Clinical studies demonstrated that tumor cell surface or membranous expression of PD-L1 correlated with the likelihood of response to therapy (p. 724, col. 1 to p. 725, col. 1). Pai teaches: “Given the high levels of membranous PD-L1 expression within HPV-HNSCC, our study supports a rationale for administering PD1:PD-L1 targeted therapy in head and neck cancer patients with the aim of reversing the anergic state induced by this immune checkpoint pathway.” (p. 725, col. 1)
Lyford-Pike essentially teaches and elaborates on the laboratory study conducted to obtain the data and conclusions discussed by Pai above. Lyford-Pike teaches determining HPV status of HNSCC patients by measuring levels of p16 by IHC. Lyford-Pike teaches measuring levels of PD-1 and PD-L1 expression in HNSCC patient tumors (Materials and Methods; Figures 1, 2; Table 1). Lyford-Pike determined “Strikingly, CD8+ TILs form HPV-HNSCC contained a distinct population of PD-1hi cells not observed among CD8+ T cells form inflamed tonsils” (p. 1736, col. 1-2). Lyford-Pike determined 70% of HPV-HNSCC samples examined had PD-L1 expression, and all of these displayed cell surface staining on 5% or more of tumor cells, whereas only 29% of HPV-negative tonsil cancers expressed PD-L1 (Table 1; p. 1736-1737). Lyford-Pike determined PD-1-expressing CD8+ TILs are functionally anergic in HPV-HNSCC. Lyford-Pike teaches while PD-L1 expression on HNSCC is variable, PD-1 is always expressed on a high proportion of TILs- much higher than on peripheral blood T cells (Figure 2; p. 1739, col. 2). Lyford-Pike teaches that PD-1 expression within the tumor microenvironment marks TILs that are functionally suppressed in their capacity to produce effector cytokines and can contribute to immune suppression (p. 1739, col. 2; Figure 6). Lyford-Pike teaches (p. 1739, col. 2 to p. 1740, col. 1):
“HPV-HNSCCs have favorable clinical outcomes with survival rates of 82% at 3 years, compared with 57% in non-HPVHNSCCs (6). Improved survival has been attributed to a younger patient age and enhanced tumor responsiveness to chemoradiation therapy. However, a contributing factor may also be the strong host immune response generated against these tumors. Evidence for inherent immunologic responses generated against HPV-HNSCC is the observed high frequency of TILs and inflammatory responses within these tumors. Indeed, HPV-HNSCC express foreign viral proteins, such as the E6 and E7 antigens, for which the host immune system should not be tolerant. Similar favorable clinical outcomes in the presence of TILs have been observed with other solid tumors including ovarian, esophageal, small cell lung, and colorectal cancers (21–24). While strong host immune responses may account for favorable clinical outcomes, the findings presented here suggest that these local immune responses induce the PD-1:PD-LI checkpoint pathway, which in turn may limit the capacity of TILs to ultimately eliminate the tumor without therapeutic intervention. The relevance of the PD-1:PD-L1 checkpoint in cancer immunity is highlighted by reports showing that blockade of PD-L1 or PD-1 by specific mAbs can reverse the anergic state of tumor-specific T cells and thereby enhance antitumor immunity.
We propose here that the PD-1:PD-L1 pathway plays a role in both persistence of HPV infection (through expression of PDL1 in the tonsillar crypt epithelium—the site of initial infection) as well as resistance to immune elimination during malignant progression. These findings extend those recently reported in melanoma (12), which is a nonvirus-associated cancer but has also been considered to be "immunogenic." Similar to melanoma, and in keeping with the proposed adaptive resistance hypothesis, PD-L1 is not expressed uniformly within HPVHNSCCs but rather at sites of lymphocyte infiltration. In contrast to melanoma, in which approximately 40% of tumors express PD-L1, the majority of HPV-HNSCC tumors (70%) and a subset of HPV-negative HNSCC (29%) are PD-L1(þ).Few PDL1() tumors, that are lymphocyte poor, have a different immune microenvironment with potential activation of alternative mechanisms of immune resistance. Given the high levels of membranous PD-L1 expression within the tumors, our studies support a rationale for administering PD-1/PD-L1–targeted therapy to the HPV-HNSCC patient population.”
Siewert teaches a method for successfully treating HPV+ and HPV- HNSCC patients with an anti-PD-1 antibody, pembrolizumab, administered 10 mg/kg every 2 weeks, wherein tumors were PD-L1 positive by IHC (slide 12 and 13). Seiwert determined that 78% of HNSCC tumors expressed PD-L1 and PD-L1 expression correlates with response to anti-PD-1 antibody pembrolizumab (slides 17 and 21).
US Patent 10,081,681, Korman, teaches and claims the known fixed dosing of 240 mg of nivolumab (BMS-936558) administered to cancer patients for immune checkpoint inhibition in cancer treatment, as well as in combination therapy with anti-CTLA-4 antibody (claims 1, 2, and 18; Figure 2A and 2B; col. 2, lines 60 to col. 3, line 4; col. 4, lines 1-37; col. 5, lines 45-60; col. 12, lines 9-50; col. 13, lines 40-63; col. 14, lines 35-40; Tables 2, 3A, 3B, 4, 6A and 6B; col. 30, lines 60-63; col. 33, lines 23-33; Examples 1-5). Korman discloses a treatment regimen of nivolumab administered at 240 mg to HPV+ head and neck cancer patients, and in combination with an additional anti-cancer therapy (BMS-986016) (Figure 2A; col. 12, lines 43-50; Table 3A). Korman teaches testing for HPV positivity by detecting p16 expression by IHC or ISH and restricting histology to squamous cell carcinoma (SCC) (col. 33, lines 23-33; Table 4). Korman reviews results from clinical trials treating several different solid tumor types with nivolumab (BMS-936558) in a wide dose range of 0.1 to 10 mg/kg every 2 weeks (Examples 1-5).
Best teaches HPV-16 is the viral type which accounts for over 90% of HPV-related oropharyngeal cancer in the United States (abstract). The overexpression of HPV oncoproteins E6 and E7 drive and maintain the neoplastic process (p. 3). Best teaches that HPV-related tumors have populations of regulatory T cells that predict lack of clinical response to therapeutic vaccination against HPV-16. Best teaches in the context of cancer immunology, the immune checkpoints can represent major obstacles to overcoming tumor-specific tolerance and generating clinically meaningful tumor control. Blockade of CTLA-4 with ipilimumab and PD-1 with nivolumab in cancer treatment are clinically practiced with success (p. 8-9).
Treatment of HPV+ and PD-L1+ HNSCC:
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat HNSCC patients in the method of NCT02105636 that are HPV+ and PD-L1+. One would have been motivated to because: 1) NCT02105636 teaches treating HNSCC patients with anti-PD-1 antibody nivolumab; 2) Pie and Lyford-Pike suggest treating the HPV+ subpopulation of HNSCC patients with PD-1:PD-L1 blockade therapy specifically because this subpopulation is demonstrate to evade anti-tumor immunity through increased PD-1 expression, enhanced PD-L1 expression, and the PD-1:PD-L1 pathway; 3) Pie and Lyford-Pike suggest treating the HPV+ subpopulation of HNSCC patients with PD-1:PD-L1 blockade therapy in order to reverse the anergic state of tumor-specific T cells and to enhance antitumor immunity; 4) Seiwert teaches that PD-L1 is expressed in 78% of HNSCC tumors and responsive to anti-PD-1 antibody treatment; and 5) Korman suggests administering nivolumab to HPV+ head and neck cancer patients specifically. One of ordinary skill in the art would have a reasonable expectation of success because: 1) NCT02105636 demonstrates nivolumab is already being clinically administered to HNSCC patients for cancer treatment; 2) Pie, Lyford-Pike, Best, and Korman teach PD-1:PD-L1 blockade therapy by nivolumab is known and successfully used clinically to treat several different tumor types; 3) Pie, Lyford-Pike, Siewert, and Best teach the mechanism of PD-1:PD-L1 blockade therapy by nivolumab or anti-PD-1 antibody to enhance anti-tumor immune responses in patients is established; and 4) Siewert demonstrated success of treating HPV+ / PD-L1+ HNSCC patients with an anti-PD-1 antibody, and demonstrated that PD-L1 expression correlated to therapeutic response.
Treating HPV+ SCCHN that express p16, Ki-67, Cyclin D1, p53, ProEx C, E6 and E7
The cited references teach that each of p16, Ki-67, Cyclin D1, p53, ProEx C, E6 and E7 are well known proteins characteristically expressed in HPV+ SCCHN and other HPV+ SCC cancers.
Conesa-Zamora teaches successful methods and known commercially available reagents for detecting and confirming expression of all of p16, cyclin D1, Ki-67, p53, and ProEx C in an HPV+ cervical cancer (Materials and Methods; Table 1; Table 2). Conesa-Zamora explains E6 and E7 are HPV viral oncoproteins expressed during HPV infection; p53 is a target of E6 oncoprotein, p16 expression is positively associated with grade of dysplasia and HPV infection; Cyclin D1 overexpression is associated with poor prognosis; Ki-67 expression is a marker of proliferating cells and associated with increasing dysplasia; and p16, Ki-67, and proEx C expression were associated with HPV-16 infection and severity of dysplasia (p. 378-379; p. 388). Conesa-Zamora teach not surprisingly, the immunohistochemical markers that show more consistent association with histologic diagnoses (i.e., p16, Ki-67, ProEx C, and cyclin D1) are related to one another (p. 388, col. 2).
Pai (above) teaches that HPV-infected cells express viral proteins E6 and E7 as antigens that are highly immunogenic to the patients.
Best (above) teaches HPV-16 is the viral type which accounts for over 90% of HPV-related oropharyngeal cancer in the United States (abstract). The overexpression of HPV oncoproteins E6 and E7 drive and maintain the neoplastic process (p. 3).
Korman (above) teaches testing for HPV positivity by detecting p16 expression by IHC or ISH and restricting histology to squamous cell carcinoma (SCC) (col. 33, lines 23-33; Table 4).
Wiest teaches HPV+ HNSCC (SCCHN), particularly HPV-16 positive, were positive for E6, E7, p16, and p53 expression (abstract; Table 1; Results; Table 3; p. 1515, col. 1-2).
Pillai teaches HPV+ HNSCC (SCCHN) were positive for E6, p53, cyclin D1, and Ki-67 expression (abstract; Results; Tables II and III). Pillai teaches the expression profile may be used to supplement or elaborate the diagnosis of oral lesions (p. 15).
Mills teaches HNSCC (SCCHN) is known to be associated with HPV infection, and teach HPV+ HNSCC is characterized by p16 and ProEx C expression (Results; Table 1). Mills teaches ProEx C is a surrogate immunohistochemical marker for HPV, and it is known that expression of E6 and E7 increases during HPV integration into the genome (p. 1159, col. 1). Mills teaches Ki-67 is a known cell proliferation biomarker (p. 1159, col. 1).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat HPV+ SCCHN tumors that express all of p16, Ki-67, Cyclin D1, p53, ProEx C, E6 and E7 in the method of NCT02105636. One would have been motivated to and have a reasonable expectation of success to because: (1) NCT02105636 teaches treating HNSCC patients with anti-PD-1 antibody nivolumab; (2) the cited combined references teach motivation and reasonable expectation of success to treat the subset of HNSCC patients that are HPV+ for the reasons set forth above; (3) Pai, Korman, Wiest, Pillai, and Mills teach that HPV+ HNSCC and other HPV+ cancers are characterized as having expression of p16, Ki-67, Cyclin D1, p53, ProEx C, E6 and E7; and (4) Conesa-Zamora, Pai, Korman, Wiest, Pillai, and Mills all demonstrate successfully detecting expression of various combinations of these proteins in HPV+ cancers utilizing commercially available antibodies and routine immunohistochemical assays. Given HPV+ HNSCC cancers are characterized by expression of p16, Ki-67, Cyclin D1, p53, ProEx C, E6 and E7, and given the cited combined art teach motivation and reasonable expectation of success for treating HPV+ HNSCC with nivolumab, it is will within the level of the ordinary skilled artisan to include subpopulations of HPV+ HNSCC patients having tumor expression of p16, Ki-67, Cyclin D1, p53, ProEx C, E6 and E7 in the population of HPV+ HNSCC patients for treatment with nivolumab because this subpopulation is encompassed by HPV+ HNSCC patients recognized by the cited art as needing, and responsive to, nivolumab treatment.
HPV-16
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat HNSCC patients in the method of NCT02105636 that are HPV-16+. One would have been motivated to and have a reasonable expectation of success to because Best teaches HPV-16 is the viral type which accounts for over 90% of HPV-related oropharyngeal cancer in the United States, therefore is established as inducing neoplasms.
Administering 240 mg
As stated above, Korman discloses a treatment regimen of nivolumab administered at 240 mg to HPV+ head and neck cancer patients.
Sadineni teaches treatment of cancers including HNSCC by administration of immune checkpoint inhibitor anti-PD-1 antibody nivolumab, and teaches administering fixed doses of the antibody at 240 mg, every 2 weeks, as well as in combination with other immune checkpoint inhibitors such as anti-CTLA-4 antibody (paragraphs [9-11, 44, 88, 105, 110, 136-138, 148, 154, 188, 189, 195, 196, 198], claim 88-96, 93, 101-103).
Bai teaches several advantages of administering fixed doses of therapeutic antibody over body weight-dependent doses (p. 132-133). Bai teaches dosing of therapeutic monoclonal antibodies (mAbs) is often based on body size, with the perception that body size-based dosing would reduce inter-subject variability in drug exposure. However, most mAbs are target specific with a relatively large therapeutic window and generally a small contribution of body size to pharmacokinetic variability. Bai conducted a study systematically evaluating the body weight-based or body weight-independent (fixed) dosing regimens for mAbs. Bai concludes mAb dosing can be flexible. Given many practical advantages, fixed dosing is recommended to be the first option in first-in-human studies with mAbs (abstract; p. 132, col. 2).
Wang teaches the advantages of administering fixed or flat doses of therapeutic antibodies for cancer treatment, particularly for first in human (FIH) clinical trials, wherein advantages include providing administration of the therapeutic antibody at the same amount regardless of patient’s demographics, offering convenience, cost-effectiveness, less risk of medical errors, and better compliance. It is more convenient to prepare and administer a unit dose to patients rather than individualizing each administration based on body size. Fixed doses also minimize wasted “left-overs” during preparation of doses (section 9.1.1.1 and 9.2).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer a fixed dose of nivolumab at 240 mg every two weeks instead of 3 mg/kg by weight every two weeks in the clinical trial of NCT02105636. One would have been motivated to because: 1) Bai and Wang teach several advantages of administering therapeutic antibodies in fixed doses, teach monoclonal antibody therapy dosing is flexible, and recommend administering fixed doses in clinical trials, 2) Korman explicitly suggests fixed dosing of nivolumab as 240 mg for HPV+ head and neck cancer patients; and 3) Sadineni suggests fixed dosing of nivolumab at 240 mg and for HNSCC patients. One of ordinary skill in the art would have a reasonable expectation of success given Korman demonstrates nivolumab is successfully administered at a wide range of doses to treat various solid tumor types, and Bai demonstrates similar pharmaceutical effects for therapeutic antibodies administered in weight-based doses versus fixed doses.
Patients have more than 70% to tumor cells showing strong and diffuse nuclear and cytoplasmic staining by IHC against p16:
Chen teaches immunohistochemical p16 staining to identify HPV positive HNSCC is known and teaches the pattern of p16 staining is associated with HPV positivity, wherein a diffuse nuclear and cytoplasmic staining pattern, regardless of intensity, is associated with HPV positivity, including no more than about 70% of tumor cells showing the staining pattern. Chen teaches previous studies have used a “cutoff of 70 % of tumor cells expressing diffuse, nuclear and cytoplasmic p16” to identify HPV positivity (abstract; Figure 1-5; p. 423, col. 1). Chen teaches: “We propose the following definitions of positive and negative p16 expression by IHC in HNSCC with strong likelihood of correlation to their respective HPV status: (1) positive — diffuse nuclear and cytoplasmic staining of the majority (≥70 %) of tumor cells, regardless of intensity of staining (when background staining is taken into consideration), and (2) negative —complete absence of staining in all tumor cells or membranous/cytoplasmic staining of rare, isolated tumor cells (≤40 % stained tumor cells) (p. 427, col. 2 to p. 428, col. 1).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for the patients identified as HPV+ in the method of the combined cited references to have more than 70% to tumor cells showing strong and diffuse nuclear and cytoplasmic staining by IHC against p16. One would have been motivated to, and have a reasonable expectation of success to, because Lyford-Pike, Korman and Chen recognize detection of p16 as a biomarker of HPV positive HNSCC, and Chen successfully demonstrate and define the immunohistochemical p16 staining pattern as identifying HPV positive HNSCC.
3. Claim(s) 32, 35, 36, 84, 90, 91 remain rejected under 35 U.S.C. 103 as being unpatentable over NCT02105636 (ClinicalTrials.gov archive, History of Changes, published April 4, 2014); Pai (Oral Oncology, 2013, 49:723-725); Lyford-Pike et al (Cancer Research, 2012, 73:1733-1741); and Seiwert et al (ASCO 2014 annual meeting, May 30-June 3, presentation slides: “A Phase 1b Study of Pembrolizumab (MK-3475) in Patients with HPV-negative and HPV-positive Head & Neck Cancer”); US Patent 10,081,681, Korman et al, claiming priority to September 2013; Best et al (Otolaryngol Clin North Am, 2012, 45:807-822, NIH Public Access Manuscript); Conesa-Zamora et al (American Journal of Pathology, 2009, 132:378-390); Wiest et al (Oncogene, 2002, 21:1510-1517); Pillai et al (Journal of Surgical Oncology, 1999, 71:10-15); Mills et al (American Journal of Surgical Pathology, 2012, 36:1158-1164); US Patent Application Publication 2016/0304607, Sadineni et al, claiming priority to April 2015; Bai et al (Clinical Pharmacokinetics, 2012, 51:119-135); Wang et al (Chapter 9 in “ADME and Translational Pharmakokinetics/Pharmacodynamics of Therapeutic Proteins: Applications in Drug Discovery and Development”, First Edition edited by Honghui Zhou and Frank-Peter Theil; Published 2016 by John Wiley & Sons, Inc.); and Chen et al (Head and Neck Pathology, 2012, 6:422-429); as applied to claims 1, 2, 11, 14, 87, and 89 above, and further in view of Callahan et al (Frontiers in Oncology, January 2015, 4: Article 385, internet pages 1-6); Jie et al (British Journal of Cancer, 2013, 109:2629-2635); and Swanson et al (Oral Oncology, January 2015, 51:12-15).
NCT02105636; Pai; Lyford-Pike; Seiwert, US Patent 10,081,681, Korman; Best; Conesa-Zamora; Wiest; Pillai; Mills; US Patent Application Publication 2016/0304607, Sadineni et al; Wang; and Chen (the combined references) teach a method for treating a subject having HPV-positive HNSCC comprising administering a flat/fixed dose of about 240 mg of nivolumab once every 2 weeks, wherein the HPV+ SCCHN comprises a tumor expressing p16, Ki-67, Cyclin D1, p53, ProEx C, E6 and E7, and wherein more than about 70% of tumor cells in the tumor show strong and diffuse nuclear and cytoplasmic staining by an immunohistochemistry against p16, as set forth above.
The combined references do not teach:
Further treating the subject with another anti-cancer agent such as an anti-CTLA-4 antibody; and
Treated patients have overall survival of at least about 10 months.
Additionally administering anti-CTLA-4 antibody therapy
As stated above, US Patent 10,081,681, Korman, teaches and claims the known fixed dosing of 240 mg of nivolumab (BMS-936558) administered to cancer patients for immune checkpoint inhibition in cancer treatment, as well as in combination therapy with anti-CTLA-4 antibody.
As stated above, Sadineni teaches treatment of cancers including HNSCC by administration of immune checkpoint inhibitor anti-PD-1 antibody nivolumab, and teaches administering fixed doses of the antibody at 240 mg, every 2 weeks, as well as in combination with other immune checkpoint inhibitors such as anti-CTLA-4 antibody.
Callahan reviews the success and motivation to combine anti-CTLA-4 antibody therapy with anti-PD-1 therapy in the clinical treatment of cancer. Callahan teaches the known success of single checkpoint blockade therapy in numerous clinical studies treating a variety of different solid tumors, including the success of nivolumab for treating head and neck cancer (Introduction; Background). Callahan teaches CTLA-4 and PD-1 are non-redundant pathways for the regulation of T cell responses, suggesting the combination could have additive or synergistic potential. A previous study demonstrated PD-1 and CTLA-4 blockade had synergistic anti-tumor activity in a mouse model of colon cancer. Another study demonstrated potent anti-tumor activity of the combination used with a cellular vaccine in a melanoma mouse model (p. 1, col. 2 to p. 2, col. 1). Callahan reviews results for combined anti-CTLA-4 antibody and nivolumab treatment clinically practiced for melanoma, renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC), wherein some patients continued nivolumab maintenance therapy at 3 mg/kg every 2 weeks after combination treatment. The clinical studies resulted in a high rate of complete responses for melanoma, significant clinical activity in RCC, and moderate response rates in NSCLC (p. 2-5). Overall survival for melanoma patients on nivolumab alone was greater than a year (Table 1), and greater than a year or 2 years with the combined therapy (Table 1).
Jie examined the expression and role of PD-1 and CTLA-4 in head and neck cancer and teaches (Discussion) “we demonstrate that the frequency of not only immune-checkpoint receptors, including CTLA-4+, TIM-3+ and PD-1+ cells, but also immune suppressive molecules, such as CD39+ and TGF-b1+ cells, were significantly increased on intratumoral Treg compared with circulating Treg. Particularly, we found that CTLA-4 and CD39 were co-expressed on the majority of intratumoral Treg, which suggests that the blockade of CTLA-4 or CD39 enzymatic activity might enhance anti-tumour immunity in the TME by inhibiting immunosuppressive activities of intratumoral Treg. We also observed that intratumoral Treg exhibited more suppressive activity than peripheral blood Treg. Taken together, this study provides insight into mechanisms and markers of intratumoral Treg, which are potently immunosuppressive cells. These CTLA-4+ /CD39+ Treg are major targets to inhibit their suppressive function, thus promoting anti-tumour immunity in the TME.”
Swanson suggests combining PD-1 and CTLA-4 blockade to treat HNSCC based on the success of combination in other cancers and their known mechanisms of treating cancer (p. 13-14).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to additionally administer CTLA-4 antibody in the method of NCT02105636. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Korman, Sadenini, Callahan, and Swanson suggest combining immune checkpoint inhibitor anti-CTLA-4 antibody with anti-PD-1 antibody therapy in order to block non-redundant pathways, and because of the success demonstrated clinically combining the two antibodies; and (2) Jie suggests treating HNSCC with anti-CTLA-4 therapy based on the known role CTLA-4 plays in immune suppression of HNSCC. One of ordinary skill in the art would have a reasonable expectation of success given: (1) the known clinical application of and success demonstrated in cancer treatment by combined anti-PD-1 and anti-CTLA-4 therapy taught by Best, Callahan, and Swanson; and (2) the known expression and roles of both PD-1 and CTLA-4 in immune suppression HNSCC taught by Pai, Lyford-Pike, and Jie.
Treatment results in an overall survival of at least about 10 months after administration
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for patients treated by the method of the combined references above to have overall survival of at least about 10 months. One would have been motivated to, and have a reasonable expectation of success to, because: (1) Pai, Korman, Callahan, and Swanson teach successful clinical response and treatment of various cancers by administration of nivolumab, as well as combinations of nivolumab with anti-CTLA-4 antibody ipilimumab; and (2) Callahan teaches nivolumab administered 3mg/kg every 2 weeks to melanoma patients resulted in overall survival longer than a year.
4. Claim(s) 35, 36, 90, 91, and 95-98 remain/are rejected under 35 U.S.C. 103 as being unpatentable over NCT02105636 (ClinicalTrials.gov archive, History of Changes, published April 4, 2014); Pai (Oral Oncology, 2013, 49:723-725); Lyford-Pike et al (Cancer Research, 2012, 73:1733-1741); and Seiwert et al (ASCO 2014 annual meeting, May 30-June 3, presentation slides: “A Phase 1b Study of Pembrolizumab (MK-3475) in Patients with HPV-negative and HPV-positive Head & Neck Cancer”); US Patent 10,081,681, Korman et al, claiming priority to September 2013; Best et al (Otolaryngol Clin North Am, 2012, 45:807-822, NIH Public Access Manuscript); Conesa-Zamora et al (American Journal of Pathology, 2009, 132:378-390); Wiest et al (Oncogene, 2002, 21:1510-1517); Pillai et al (Journal of Surgical Oncology, 1999, 71:10-15); Mills et al (American Journal of Surgical Pathology, 2012, 36:1158-1164); US Patent Application Publication 2016/0304607, Sadineni et al, claiming priority to April 2015; Bai et al (Clinical Pharmacokinetics, 2012, 51:119-135); Wang et al (Chapter 9 in “ADME and Translational Pharmakokinetics/Pharmacodynamics of Therapeutic Proteins: Applications in Drug Discovery and Development”, First Edition edited by Honghui Zhou and Frank-Peter Theil; Published 2016 by John Wiley & Sons, Inc.); and Chen et al (Head and Neck Pathology, 2012, 6:422-429); as applied to claims 1, 2, 11, 14, 87, and 89 above, and further in view of Kiyota et al (Jpn J Clin Oncol, 2012, 42:927-933); Tahara et al (International Journal of Radiation Oncology, Biology, Physics, 2014, Vol. 88, Issue 2:P509-519; abstract #265); and Antonia et al (International Journal of Radiation Oncology, Biology, Physics, March 23, 2015; Vol. 90, Issue 5; p. S2; abstract 3).
NCT02105636; Pai; Lyford-Pike; Seiwert, US Patent 10,081,681, Korman; Best; Conesa-Zamora; Wiest; Pillai; Mills; US Patent Application Publication 2016/0304607, Sadineni et al; Wang; and Chen (the combined references) teach a method for treating a subject having HPV-positive HNSCC comprising administering a flat/fixed dose of about 240 mg of nivolumab once every 2 weeks (day 1 and 15), wherein the HPV+ SCCHN comprises a tumor expressing p16, Ki-67, Cyclin D1, p53, ProEx C, E6 and E7, and wherein more than about 70% of tumor cells in the tumor show strong and diffuse nuclear and cytoplasmic staining by an immunohistochemistry against p16, as set forth above.
As stated above, NCT02105636 teaches the Inclusion Criteria for HNSCC patient treatment with nivolumab is “Tumor progression or recurrence within 6 months of last dose of platinum therapy in the adjuvant (ie with radiation after surgery), primary (ie, with radiation), recurrent, or metastatic setting (p. 5).
The combined references do not teach:
Further administering standard of care cisplatin chemotherapy or platinum-based doublet therapy.
The platinum chemotherapy that the HNSCC patients are relapsing from or refractory to comprises cisplatin.
Kiyota teaches cisplatin chemotherapy is the standard of care for HNSCC (abstract).
Tahara teaches cisplatin/5-FU doublet chemotherapy is the standard of care for HNSCC.
Antonia teaches successful combination of nivolumab with standard platinum doublet therapy, including therapy comprising cisplatin, for treating NSCLC patients.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to additionally administer standard platinum-doublet therapy and/or cisplatin therapy after nivolumab treatment in order to treat HNSCC in the method of the combined references. One would have been motivated to, and have a reasonable expectation of success to, because Kiyota and Tahara teach that cisplatin and platinum doublet therapy are established standard of care of HNSCC patients, and Antonia teaches nivolumab has been successfully combined with standard care cisplatin or platinum doublet therapy to treat other cancers.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed for the platinum-based chemotherapy of the refractory/resistant HNSCC patients to comprise cisplatin. One would have been motivated to, and have a reasonable expectation of success to, because: (1) NCT02105636 teaches the Inclusion Criteria for HNSCC patient treatment with nivolumab is “Tumor progression or recurrence within 6 months of last dose of platinum therapy in the adjuvant (ie with radiation after surgery), primary (ie, with radiation), recurrent, or metastatic setting”; and (2) Kiyota and Tahara teach that cisplatin was established in the platinum-based chemotherapy standard of care of HNSCC patients.
Response to Arguments
5. Applicants argue that the claims are 81-81 and 92-94 are canceled, and claims 1 and 2 are amended to recite that the HPV+ SCHHN is recurrent or metastatic, and the subject is resistant or refractory to a previous cancer therapy comprising platinum-based chemotherapy. Applicants argue the cited combined references of the rejection do not provide a reasonable expectation that the claimed methods would be effective at treating patients afflicted with a recurrent or metastatic HPV-positive SCCHN, which is resistant or refractory to a previous cancer therapy comprising a platinum based chemotherapy. Applicants argue that the only reference that the Examiner alleges discloses treating patients afflicted with a recurrent or metastatic HPV-positive SCCHN, which is resistant or refractory to a previous platinum based chemotherapy is NCT02105636. However, NCT02105636 does not teach or suggest administering a flat dose of 240 mg nivolumab every two weeks, as recited by amended claims 1 and 2, and NCT02105636 provides no evidence suggesting that administering 240 mg to the claimed patient population would be effective. Rather, NCT02105636 is merely a clinical trial protocol, which does not disclose a flat dose of 240 mg, and which does not disclose any data. Data arising from NCT02105636 only published after the priority date of the present claims. Applicants argue that Examiner points to no other reference that would provide a skilled artisan with any reason to expect that the claimed methods would be effective in treating the recited patient population. As such, at the time the present application was filed, a person of ordinary skill in the art would not have had a reasonable expectation that the claimed methods would be effective at treating the recited patient population.
6. The arguments have been considered but are not persuasive. Applicants have argued the individual NCT02105636 reference. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller , 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually. Where an applicant’s reply establishes that each of the applied references fails to teach a limitation and addresses the combined teachings and/or suggestions of the applied prior art, the reply as a whole does not attack the references individually as the phrase is used in Keller and reliance on Keller would not be appropriate. This is because "[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA]." In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012).
In the instant rejection, NCT02105636 teaches the limitations recently amended into claims 1 and 2 for treating SCCHN patients that are recurrent/refractory after platinum based chemotherapy and who are recurrent/metastatic by administration of nivolumab. Secondary references Bai, Wang, Korman, and Sadineni provided both motivation and reasonable expectation of success to administer the nivolumab as a flat 240 mg dose once every two weeks for the reasons of record. Applicants did not address these references or the obviousness reasoning provided in the rejection.
Although Applicants argue that NCT02105636 did not provide resultant data after treatment, and argue that it is “merely a clinical trial protocol”, Examiner notes NCT02105636 is not “merely a clinical trial protocol”, but rather, is a disclosure of a PHASE 3 clinical trial of nivolumab in recurrent or metastatic platinum refractory SCCHN patients that was already started in April 2014 (p. 3). NCT02105636 teaches the treatment was being applied clinically, and was already moved into Phase 3.
7. All objections recited in the Office Action mailed April 18, 2025 are hereby withdrawn in view of amendments. The double patenting rejection over U.S. Patent No. 10,544,224 recited in the Office Action mailed April 18, 2025 is hereby withdrawn in view of the terminal disclaimer filed.
8. Conclusion: No claim is allowed.
Conclusion
9. THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642