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 .
Response to Amendment
The Amendments and Remarks filed 02/12/2026 in response to the Office Action of 10/16/2025 are acknowledged and have been entered.
Claims 1, 8, 42, 43, 44, 48, 53, 55, 56, 74, 145, 146 and 148 have been amended by Applicant.
Claims 1, 8, 15, 16, 42-44, 48, 53, 55-56, 74, 145-146 and 148 are currently under examination on the merits.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 02/12/2026, are being considered by the examiner.
Drawings Objection - Withdrawn
Applicant has cited in the Remarks that the specification in Example 1 discloses that all seven peptides from Table 1 were administered in FIG. 2. Therefore, the objection has been withdrawn.
Claim objections - Withdrawn
Applicant has amended claim 42 9 and so the objection has been withdrawn.
Claim Rejections – Withdrawn
Claim Rejections - 35 USC § 112(b) - Withdrawn
Given that Applicant has now amended claims 8, 55 and 148, the 112(b) rejections of these claims are hereby withdrawn.
Claim Rejections - 35 USC § 112 (a) Written Description - Withdrawn
Given that Applicant has now amended claims 55 and 148 to recite tumor antigen peptides in claim 55 and HPV viral antigenic peptides in claim 148, the 112(a) written description rejection of claims 55 and 148 is hereby withdrawn.
Claim Rejections - 35 USC § 103 (fourth) - Withdrawn
Given that Applicant has now amended claim 8 to recite peptides of SEQ ID NO.s 11-17 and amended claim 55 to recite tumor antigens of SEQ ID NO.s 11-17 in the claims, the rejection of claims 1, 8, 15, 16, 42, 43, 44, 48, 55, 74, 145 and 146 under 35 U.S.C. 103 as being unpatentable over Gelfand et al. (EP3329931A1 Date Published 2018-06-06), Chowdhury and Honjo (Journal of Internal Medicine, 2018, 283; 110–120) and Wu et al. (US20180141983A1 Date Published 2018-05-24) as applied to claims 1, 15, 16, 42, 43, 44, 48, 74, 145, and 146 above and further in view of Schuster et al. (WO2018138257A1 Date Published 2018-08-02) has been withdrawn.
Double Patenting –(second Application No. 17/930,219) - Withdrawn
The provisional nonstatutory double patenting rejection of claims 1, 15, 16, 42, 43, 44, 53 and 74 as being unpatentable over claims 27, 28, 29, 34-39 and 41-45 of copending Application No. 17/930,219 has been withdrawn. This is because the copending Application No. 17/930,219 has been abandoned (due to failure to respond to an Office Action).
Claim Rejections – Maintained
Claim Rejections - 35 USC § 112(a) Scope of Enablement - Maintained
Claims 16 and 74 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a method for treating HPV-induced cancers comprising administering to a subject an effective amount of a pharmaceutical composition of claim 1, does not reasonably provide enablement for similar methods for treating and “preventing” just any cancer comprising administering to just any subject an effective amount of a pharmaceutical composition of claim 1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to perform the process of the invention commensurate in scope with these claims.
Claims 16 and 74, as written, include methods of preventing cancer in an individual predisposed to cancer. The specification lacks guidance and or objective evidence with regards to vaccination of a population of subjects predisposed to any cancer other than HPV-related cancer. On Pg. 23 of the instant specification, it discloses that a therapeutic that "prevents" a condition (e.g., cancer) refers to a composition that, when administered to a statistical sample prior to the onset of the disorder or condition, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample. The specification also discloses in Example 1 (Pg. 83 line 21 to Pg. 84 line 25) and Figure 2 the effects of Self-Assembling Vaccines (SAVs) cancer vaccine on mice previously injected with ovarian cancer cells as a treatment method either alone or in combination with anti-PD-1 antibody. The specification further discloses murine model systems were used to study the effects of the SAVs for the treatment of ovarian cancer using the ID8 model (Example 2 Pg. 85 lines 4-32) and HPV-related cancers using the Tc-1 model (Example 3 Pg. 86-87) however no data was provided into the results from testing in said models. Therefore, tests for and results from the treatment of cancers were disclosed but not for those relating to the prevention of cancers.
It is well known in the art that the prevention of cancer, in general, is highly unpredictable and applicant have not demonstrated, with any predictability, that the claimed pharmaceutical composition would predictably prevent the occurrence of just any cancer other than HPV-related cancers. Reasonable guidance with respect to preventing any cancer relies on quantitative analysis from defined populations; some of which have been successfully pre-screened and are predisposed to particular types of cancer. This type of data might be derived from widespread genetic analysis, cancer clusters, family histories, or randomized controlled trials. For example, Byers, T. (CA Cancer Journal for Clinicians, Vol. 49, No. 6, Nov/Dec. 1999) teaches that randomized controlled trials are commonly regarded as the definitive study for proving causality (1st col., p.358), and that in controlled trials the random assignment of subjects to the intervention eliminates the problems of dietary recalls and controls the effects of both known and unknown confounding factors. Further, Byers suggests that chemo-preventative trials be designed “long-term” such that testing occurs over many years (2nd col., p. 359). Further, the essential element towards the validation of any preventive therapeutic is the ability to test the drug on subjects monitored in advance of clinical cancer. This would require monitoring a large population with the claimed agents and linking such results with subsequent histological confirmation of the presence or absence of disease. Thus, while the specification is enabling for preventing HPV-related cancers in a patient, the specification lacks reasonable guidance, predictability, and objective evidence that enables the prevention of cancer other than HPV-related cancers.
Response to Arguments
In the reply of 02/12/2026, Applicant cites the claims as amended are directed to a combination of the SAV and an immunotherapy. Example 1 of the application describes results from an experiment in which mice injected with cancer cells were administered the SAV, an immunotherapy (an anti-PD-1 antibody), or the combination of both. As described at page 84, lines 9-13 of the specification as filed, immunological studies of tumor infiltrating lymphocytes were conducted, and it was found that administration of the SAV in combination with the anti-PD-1 antibody generated the highest levels of immune cell proliferation of all treatment groups which, at least in part, contributed to the improved survival of this arm of the study compared to the mice receiving the SAV or anti- PD-1 antibody alone. Together, these results demonstrate that administration of an SAV in combination with an immunotherapy increases proliferation of anti-cancer immune cells. Accordingly, in view of these data, a person of skill in the art would expect that an SAV in combination with an immunotherapy would be useful for conferring protective immunity and preventing cancer.
Examiner’s Response: The arguments found in the Reply of 02/12/2026 have been carefully considered but are not deemed persuasive. This is because the specification in Example 1 and FIG. 2 has not disclosed data that support administration of the SAV and anti-PD-1 antibody therapy to prevent cancer. The title of Example 1 “Treatment of Ovarian Cancer” indicates that the therapy investigated whether ovarian cancer could be treated with the said administration. In addition, the data in FIG. 2 showed the probability of survival in treated subjects, not data on the decrease in numbers of tumors or the lack of tumors in treated subjects.
With regards to the citation that “As described at page 84, lines 9-13 of the specification as filed, immunological studies of tumor infiltrating lymphocytes were conducted”, the Examiner notes that this is on Pg 84 lines 21-25. The specification discloses “In immunological studies of tumor infiltrating lymphocytes, it was found that administration of the SAV/anti-PD-1 antibody combination generated the highest levels of immune cell proliferation of all treatment groups and which, at least in part, contributes to the improved survival of this arm of the study compared to the mice receiving other treatments”. This statement is acceptable to corelate the increased levels of tumor infiltrating lymphocyte proliferation to the improved survival rates. However, an extrapolation or expectation that the increased proliferation of anti-cancer immune cells from the administration of SAV in combination with an immunotherapy would be useful for conferring protective immunity and preventing cancer has to be corroborated by evidence since it is well known in the art that the prevention of cancer, in general, is highly unpredictable.
Claim Rejections - 35 USC § 103(first) – Maintained
Claim(s) 1, 15, 16, 42, 43, 44, and 74 are rejected under 35 U.S.C. 103 as being unpatentable over Gelfand et al. (EP3329931A1 Date Published 2018-06-06) in view of Chowdhury and Honjo (Journal of Internal Medicine, 2018, 283; 110–120).
Gelfand et al. teaches pharmaceutical compositions comprising a heat shock protein fused to a biotin-binding protein, wherein the biotin-binding protein is non-covalently bound to biotinylated components (Abstract). Gelfand et al. also teaches that the pharmaceutical compositions are self-assembled vaccines comprising the heat shock fusion protein and the biotinylated component (Figure 15). They teach the biotinylated component is a biotinylated cell or a biotinylated virus (claim 2) or a biotinylated antigen (claim 3) or biotinylated peptides (Figure 13). They also teach the term "cell" when used in the context as an antigen-containing biotinylated component is intended to encompass whole cells or portions thereof, provided that the portions contain the antigen of interest on a surface accessible for recognition by the immune system when a pharmaceutical composition comprising the biotinylated "cell" is administered to a subject (Paragraph [0021]). They further teach that an example of such a cell is a tumor cell, including tumor cells from ovarian cancer to be treated or prevented by the methods of their invention (Paragraphs [0069] and [0070]).
Gelfand et al. also teaches that the heat shock protein fusion and biotinylated components can be administered to a subject to induce or enhance immune response, particularly a cell-mediated cytolytic response, against a cell expressing an antigen against which the biotinylated components are directed, serving as an immunogenic composition, or confer protective immunity as a vaccine (Paragraph [0129].
Gelfand et al. does not specifically teach a composition comprising an immunotherapy. They also do not specifically teach a method comprising conjointly administering to the subject an immunotherapy. However, these deficiencies are made up in the teachings of Chowdhury and Honjo.
Chowdhury and Honjo teach that immunotherapy using PD-1 blockade has provided durable effects against a wide variety of cancers with limited adverse effects (Abstract). They teach that cancer vaccines can be combined with PD-1 blockade because such a combination approach is logical due to PD-1 blockade being accepted as a standard treatment in various types of cancer (Pg. 113 Column, first, Paragraph, first, Lines 6-11).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making and administering to a subject with cancer an effective amount of a pharmaceutical composition that comprises a heat shock protein fused to a biotin-binding protein vaccine, wherein the biotin-binding protein is non-covalently bound to a biotinylated tumor cell or a biotinylated tumor antigen as taught by Gelfand et al. and an immunotherapy as taught by Chowdhury and Honjo for treating cancer in a subject because Chowdhury and Honjo teaches that PD-1 blockade could provide a boost to the natural immune response which when combined with cancer vaccines may be a reasonable approach for the treatment of less immunogenic tumors (Pg. 115 Column, first, Paragraph, third, Lines 3-7). This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (second) - Maintained
Claim(s) 1, 15, 16, 42, 43, 44, 53 and 74 are rejected under 35 U.S.C. 103 as being unpatentable over Gelfand et al. (EP3329931A1 Date Published 2018-06-06) and Chowdhury and Honjo (Journal of Internal Medicine, 2018, 283; 110–120) as applied to claims 1, 15, 16, 42, 43, 44, and 74 above and further in view of Yu et al. (Biochemical and Biophysical Research Communications 494 (2017) 13-19).
The combined teachings of Gelfand et al. and Chowdhury and Honjo in the first 103 above render obvious instant claims 1, 15, 16, 42, 43, 44 and 74, as discussed above.
Gelfand et al. and Chowdhury and Honjo do not explicitly teach the pharmaceutical composition comprising (a) a heat shock protein fused to a biotin-binding protein, wherein the biotin-binding protein is non-covalently bound to a biotinylated peptide, and wherein the peptide: (1) binds to a MHC class I molecule; and (2) has less than 100% homology to an autologous native sequence and/or a native microbiome sequence. They also do not teach wherein the biotin-binding protein is non-covalently bound to a biotinylated tumor antigen derived from an ovarian cancer cell. They also do not specifically teach a method of preventing and/or treating cancer in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition of claim 1, wherein, when the biotin-binding protein is non-covalently bound to a biotinylated peptide, the cancer is ovarian cancer. However, these deficiencies are made up in the teachings of Yu et al.
Yu et al. teaches a recombinant protein MtHSP70-CLIC1 comprising from the carboxyl terminus of mycobacterium tuberculosis HSP70 (MtHSP70) conjugated to the extracellular domain of chloride intracellular channel 1 (CLIC1), a tumor marker for ovarian cancer (Abstract). Yu et al. also teaches that the recombinant fusion protein of MtHSP70-CLIC1 is used in dendritic cell-based vaccine for the treatment of ovarian cancer (Pg. 14 Section 2.3 and Pg. 15-16 Section 3.5). They teach that the fusion protein vaccine increases immune response and CTL proliferation and implies that MtHSP70-CLIC1 binds to MHC I class molecules (Pg. 16 Column, second, Paragraph first, and Pg. 18, Column, first, Paragraph, second). In addition, they teach that mutated antigens are more specific and should elicit more potent immune responses suggesting the use of mutated tumor-associated antigens that intrinsically have less than 100% homology to native autologous sequence (Pg. 18 Column, first, Paragraph, first, Lines 7-9).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making and using a pharmaceutical composition that comprises a heat shock protein fused to a biotin-binding protein, wherein the biotin-binding protein is non-covalently bound to a biotinylated peptide as taught by Gelfand et al. and comprises the ovarian cancer specific tumor antigenic peptide of CLIC1 or mutants that binds to a MHC class I molecule as taught by Yu et al. as the biotinylated peptide, further comprising the anti-PD-1 immunotherapy as taught by Chowdhury and Honjo, for treating ovarian cancer in a subject because Yu et al. teaches that the combination of MtHsp70 and CLIC1 in a vaccine promotes the phenotypic and functional maturation of DCs in vitro, thus enhancing the antigenicity of CLIC1 to induce a more potent antitumor effect against CLIC1-expressing ovarian cancer cells than MtHsp70 or CLIC1 alone (Pg. 18 Column, second, Paragraph, first). This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (third) - Maintained
Claim(s) 1, 15, 16, 42, 43, 44, 48, 56, 74, 145, and 146 are rejected under 35 U.S.C. 103 as being unpatentable over Gelfand et al. (EP3329931A1 Date Published 2018-06-06) in view of Chowdhury and Honjo (Journal of Internal Medicine, 2018, 283; 110–120) and Wu et al. (US20180141983A1 Date Published 2018-05-24).
Gelfand et al. teaches pharmaceutical compositions comprising a heat shock protein fused to a biotin-binding protein, wherein the biotin-binding protein is non-covalently bound to biotinylated components (Abstract). Gelfand et al. also teaches that the pharmaceutical compositions are self-assembled vaccines comprising the heat shock fusion protein and the biotinylated component (Figure 15). They teach that the biotinylated component is a biotinylated cell or a biotinylated virus (claim 2). They also teach that the cell can be a tumor cell that is from cervical cancer (Paragraphs [0069] and [0070]) or the cell can be whole cells or portions thereof that contain an antigen of interest on a surface (Paragraph [0021]). They further teach that antigenic viruses include Human papilloma viruses (Paragraph [0077]). Gelfand et al. also teaches that the term "virus" when used in the context as an antigen-containing biotinylated component is intended to encompass whole viral particles or portions thereof, provided that the portions contain the antigen of interest on a surface accessible for recognition by the immune system when a pharmaceutical composition comprising the biotinylated "virus" is administered to a subject (Paragraph [0048]).
Gelfand et al. does not specifically teach a pharmaceutical composition comprising an immunotherapy. They also do not specifically teach the pharmaceutical composition wherein the biotinylated tumor antigen comprises a protein or an immunogenic fragment thereof that is derived from a tumor-producing virus, or wherein the biotin-binding protein is non-covalently bound to a biotinylated HPV viral antigen. However, these deficiencies are made up in the teachings of Chowdhury and Honjo and Wu et al.
Chowdhury and Honjo teach that immunotherapy using PD-1 blockade has provided durable effects against a wide variety of cancers with limited adverse effects (Abstract). They teach that cancer vaccines can be combined with PD-1 blockade because such a combination approach is logical due to PD-1 blockade being accepted as a standard treatment in various types of cancer (Pg. 113 Column, first, Paragraph, first, Lines 6-11).
Wu et al. teach a pharmaceutical composition comprising a nucleic acid encoding a fusion polypeptide comprising HSP70 from Mycobacterial tuberculosis fused in frame with an antigenic peptide (Paragraphs [0012] and [0028]). They teach that the antigenic peptide is non-oncogenic mutated E7 or E6 polypeptides from human papillomavirus HPV-16 (claims 7-13). Wu et al. also teach immunogenic constructs comprising HPV E7 as the model antigen (Paragraph [0011] and [0012]). They also teach that the pharmaceutical compositions are used as a vaccine to enhance an antigen-specific immune response and T cell proliferation mediated by CD8 cytotoxic lymphocytes (Abstract, claims 24 and 28, and Paragraphs [0038] and [0076]). They further teach in claims 37-40 and Paragraphs [0038], [0039], [0097] and [0188] that the pharmaceutical compositions exert anti-tumor effects such as inhibiting and preventing growth of a tumor expressing HPV polypeptides E7 or E6 in humans (it is noted that E7 and E6 are well known in the art as tumor antigens).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making and administering to a patient with E7 or E6-expressing cancer a therapeutically effective amount of a pharmaceutical composition that comprises a heat shock protein fused to a biotin-binding protein vaccine, wherein the biotin-binding protein is non-covalently bound to a biotinylated component as taught by Gelfand et al. and comprises an E6 or E7 antigenic/immunogenic fragments from HPV as taught by Wu et al.; or a biotinylated HPV-expressing tumor cell as the biotinylated component (because Gelfand et al. teaches the biotinylated component can be a cell expressing an antigen of interest and Wu et al. teaches tumor cells expressing E7 or E6 antigen); further comprising an anti-PD-1 immunotherapy as taught by Chowdhury and Honjo for treating HPV-related cancers in a subject because Chowdhury and Honjo teaches that PD-1 blockade could provide a boost to the natural immune response which when combined with cancer vaccines may be a reasonable approach for the treatment of less immunogenic tumors (Pg. 115 Column, first, Paragraph, third, Lines 3-7), and Wu et al. teach that the fusion or combination of HSP70 and E7 enhances the potency of vaccines via CD8-dependent pathways and improves antigen-specific antitumor effects (Paragraphs [0226] and [0230]). This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (Fifth) - Maintained
Claim(s) 1, 15, 16, 43, 44, 48, 56, 74, 145 and 146 are rejected under 35 U.S.C. 103 as being unpatentable over Gelfand et al. (EP3329931A1 Date Published 2018-06-06), Chowdhury and Honjo (Journal of Internal Medicine, 2018, 283; 110–120) and Wu et al. (US20180141983A1 Date Published 2018-05-24) as applied to claims 1, 15, 16, 43, 44, 48, 56, 74, 145, and 146 above and further in view of Sanders et al. ("Inactivated viral vaccines" in Vaccine analysis: strategies, principles, and control. Berlin, Heidelberg: Springer Berlin Heidelberg, 2014. 45-80.).
The combined teachings of Gelfand et al., Chowdhury and Honjo and Wu et al. in the third 103 above render obvious instant claims 1, 15, 16, 43, 44, 48, 56, 74, 145, and 146, as discussed above.
Gelfand et al., Chowdhury and Honjo and Wu et al. do not explicitly teach the pharmaceutical wherein the biotinylated HPV virus is an inactivated HPV virus. However, this deficiency is made up in the teachings of Sanders et al.
Sanders et al. teaches inactivated viral vaccines (Title) and that the foundations of immunization with inactivated virus preparations were laid at the end of the nineteenth century with Pasteur’s partially inactivated rabies virus (Pg. 45 Section 2.1 specifically Lines 9-10). They teach various techniques in achieving inactivation of viruses as vaccines for human (Sections 2.2, 2.4 and 2.6).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making and administering to a patient with an HPV-expressing cancer a therapeutically effective amount of a pharmaceutical composition that comprises a heat shock protein fused to a biotin-binding protein, wherein the biotin-binding protein is non-covalently bound to a biotinylated component is a whole of partial HPV virus as taught by Gelfand et al. and the virus is an inactivated virus as taught by Sanders et al., further comprising an anti-PD-1 immunotherapy as taught by Chowdhury and Honjo for treating HPV-related cancers in a subject because Sanders et al. teaches that vaccines that comprise inactivated viruses possess a higher safety profile as compared to live vaccines, as well as generally being less reactogenic (Pg. 49 lines 3-4). This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (Sixth) - Maintained
Claim(s) 1, 15, 16, 43, 44, 48, 56, 74, 145, 146 and 148 are rejected under 35 U.S.C. 103 as being unpatentable over Gelfand et al. (EP3329931A1 Date Published 2018-06-06), Chowdhury and Honjo (Journal of Internal Medicine, 2018, 283; 110–120) and Wu et al. (US20180141983A1 Date Published 2018-05-24) as applied to claims 1, 15, 16, 43, 44, 48, 56, 74, 145, and 146 above and further in view of Hedley et al. (WO200119408A1 Date Published 2001-03-22).
The combined teachings of Gelfand et al., Chowdhury and Honjo and Wu et al. in the third 103 above render obvious instant claims 1, 15, 16, 43, 44, 48, 56, 74, 145, and 146, as discussed above.
Gelfand et al., Chowdhury and Honjo and Wu et al. do not explicitly teach the pharmaceutical wherein the biotinylated HPV viral antigen is selected from Table 3. However, these deficiencies are made up in the teachings of Hedley et al.
Hedley et al. teaches nucleic acids encoding polyepitope polypeptides containing multiple epitopes from one or more proteins that are useful as treatments for tumors (Abstract). They teach in Table 3 peptides with the sequences of SEQ ID NO: 94 and 92 that are HPV 16 MHC-binding epitopes (Pg. 21).
SEQ ID NO: 94 of Hedley et al. is an exact match to instant SEQ ID NO: 6 which consists of the 10 amino acid sequence of VYDFAFRDLC, while SEQ ID NO: 92 of Hedley et al. (EVYDFAFRDL; also 10 amino acids in length) has an 84.2% identity match to instant SEQ ID NO: 6 (as shown below). Based on the broad definition of what is included in Table 3 (see lines 26-30 on page 38 of the instant specification), SEQ ID NO:92 of Hedley et al. is a peptide of Table 3.
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One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of making and administering to a patient with E7 or E6-expressing cancer a therapeutically effective amount of a pharmaceutical composition that comprises a heat shock protein fused to a biotin-binding protein, wherein the biotin-binding protein is non-covalently bound to a biotinylated component as taught by Gelfand et al. and comprises an HPV 16 E6 or E7 immunogenic peptide as taught by Hedley et al. as the biotinylated component, further comprising an anti-PD-1 immunotherapy as taught by Chowdhury and Honjo for treating HPV-related cancers in a subject because Hedley et al. teaches that an advantage of using the partial sequence of HPV E6 or E7 protein is that it permits delivery of said peptides to MHC class I molecules that can avoid problems associated with interference of antigen presentation by full length or fragments of viral proteins, or deleterious effects seen in over-expression of certain viral proteins (Pg. 14 Lines 4-8). This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Taken all together, the combination of art above clearly renders the claimed inventions above as a whole prima facie obvious.
Response to Arguments
In the reply of 02/12/2026, Applicant cites the claims have been amended to be directed to a combination of the SAV and an immunotherapy. Example 1 of the application describes results from an experiment in which mice injected with cancer cells were administered the SAV, an immunotherapy (an anti-PD-1 antibody), or the combination of both. As evidenced in FIG. 2, survival rates of mice in the combination treatment group were significantly improved compared to those treated with either the SAV or anti-PD-1 antibody alone. See, e.g., page 84, lines 3-5 of the specification as filed, "[t]he most substantial improvement in survival was observed in those mice treated with the combination of SAV cancer vaccine and anti-PD-1 antibody, where 3 of 7 mice lived to beyond 100 days".
In addition, Applicant cites that importantly, the synergistic effects of the SAV in combination with the anti-PD-1 antibody were found to be, at least in part, due to the superior ability of the combination treatment to stimulate immune cell proliferation (see, e.g., page 10, lines 24-33 and page 84, lines 9-13 of the specification as filed). Immune cells that have become exhausted in the fight against an infection or tumor often have high levels of PD-1 on their surface. Anti-PD-1 antibodies can bind the surface of these low-functioning immune cells and re- invigorate them. However, treatment with an anti-PD-1 antibody does not increase the number of anti-cancer immune cells in the body. Indeed, it is the SAV that expands the number of anti-cancer immune cells, at least in part, due to the presence of the heat shock protein, which has known immune stimulating properties (see, e.g., page 9, line 33). Surprisingly, the combination of the SAV (to increase proliferation of anti-cancer immune cells) together with an immunotherapy (to restore and maintain immune cell function) produces superior results than with either approach alone.
Further, Applicant cites that the synergistic combination of an SAV and an immunotherapy in expanding immune cells is unexpected in view of Gelfand and Chowdhury, viewed alone or in combination. As acknowledged by the Examiner, Gelfand does not teach an immunotherapy. Chowdhury does not teach or suggest a pharmaceutical composition comprising the combination of a heat shock protein fused to a biotin-binding protein, in which the biotin-binding protein is non-covalently bound to a biotinylated peptide, a biotinylated tumor cell, a biotinylated tumor antigen, a biotinylated HPV virus, or a biotinylated HPV viral antigen, and an immunotherapy as presently claimed, much less the unexpectedly improved effect of the claimed combination as demonstrated above by the instant application. None of the cancer vaccines described in Chowdhury include a heat shock protein as presently claimed. In addition, none of Yu, Wu, Schuster, Sanders, or Hedley remedy the deficiencies of Gelfand and Chowdhury. Accordingly, the skilled artisan would not have been able to predict the surprising technical effect associated with the instant claims. Thus, the present claims are characterized by the unexpectedly advantageous properties associated with the recited combination of SAV with an immunotherapy.
Examiner’s Response: The arguments found in the Reply of 02/12/2026 have been carefully considered but are not deemed persuasive. This is because:-
(1) the evidence provided in the specification is not commensurate in scope with the claims. To elaborate, the evidence provided in FIG. 2 used a vaccine with peptides of Table 1, however the rejected claims do not require that the SAV comprises any one of the peptides in Table 1 which are now recited in claims 8 and 55. See MPEP 716.02(d): the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980); and
(2) combining PD-1 inhibition with vaccines is known to provide synergistic results. For instance, Massarelli et al. teaches a phase 2 clinical trial of nivolumab (anti-PD-1 antibody) and human papillomavirus 16 vaccine ISA101 (a tumor-specific human papillomavirus 16-related cancer vaccine) which showed a 33% overall response rate (8 of 24 patients), compared with response rates of 16% to 22% with anti-PD-1 alone in similar patients (Key Points and Abstract; Massarelli et al. JAMA Oncol. 2019;5(1):67–73). Moreover, Ali-Saab et al. teaches that mice bearing B16 melanoma tumors received treatment with PD-1 antibodies combined with a single dose cancer vaccination significantly reduced the rate of tumor progression and resulted in long-term survival rates of 40%, with complete tumor regression in the surviving mice (Fig. 1A–C), whilst treatment with PD-1 antibody alone had no effect on tumor progression and survival outcomes in these animals (Supplementary Fig. S1) and a single cancer vaccination only modestly suppressed tumor progression but did not effect long-term survival in any mice bearing B16 melanoma tumors (Fig. 1) (Ali-Saab et al. Cancer Immunol Res. 2016 Feb;4(2):95-100).
In addition, from teachings such as Cappuccini et al (Cancer Immunol Immunother, 2016, 65: 701-713), it is well-known that administering a cancer vaccine comprising a tumor antigen induces an antigen-specific immune-stimulatory effect therapeutic response and that the therapeutic response from the vaccine is greatly enhanced by administering a PD-1 blocking antibody (Abstract, in particular). Cappuccini et al cites numerous studies teaching anti-tumor activities of cancer vaccines increase when combined with antibodies blocking PD-1 or PD-L1 (page 711, in particular). Mkrtichyan et al (Journal for Immunotherapy of Cancer, 2013, 1(15): 1-9), cited by Cappuccini et al, further demonstrates cancers that are relatively non-responsive to checkpoint-inhibitor treatment (“aPD-1”) monotherapy wherein the checkpoint-inhibitor treatment alone does not induce infiltration of CD8+ T cells (Figures 2-3, in particular). However, treating said cancers by administering a combination of a PD-1 inhibitor and anti-tumor antigen cancer vaccine (“Lm-LLO-E7 + aPD-1”) clearly demonstrates synergistic therapeutic benefit wherein the PD-1 inhibitor greatly enhances the therapeutic potency of the vaccine by at least two-fold, increases the antigen-specific immune response by two-fold, synergistically increases the level of tumor-infiltrated CD8+ T cells by two-fold within the tumor microenvironment, results in a synergistic increase in percent survival and decrease in tumor volume as compared to administering either component alone (Figures 2-3, in particular).
Double Patenting - Maintained
First NSDP Maintained: U.S. Patent No. 10800837
Claims 1, 15, 16, 42, 43, 44, 53 and 74 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9, 11, 12, 14 and 17 of U.S. Patent No. 10800837 in view of Chowdhury and Honjo (Journal of Internal Medicine, 2018, 283; 110–120).
Patented claim 1 is drawn to a pharmaceutical composition comprising a heat shock protein fused to a biotin-binding protein, wherein the biotin-binding protein is non-covalently bound to a biotinylated tumor cell or a biotinylated tumor antigen.
Patented claim 9 recites the pharmaceutical composition of claim 1, wherein the biotin-binding protein is non-covalently bound to a biotinylated tumor cell; and the biotinylated tumor cell expresses an antigen on its surface.
Patented claim 11 recites the pharmaceutical composition of claim 9, wherein the biotinylated tumor cell is a biotinylated fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewings tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, colorectal cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, Sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, testicular tumor, lung carcinoma, Small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, cranio pharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, polycythemia Vera, lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, or heavy chain disease cell.
Patented claim 12 recites the pharmaceutical composition of claim 9, wherein the biotinylated tumor cell is a biotinylated ovarian cancer cell.
Patented claim 14 recites, the pharmaceutical composition of claim 1, wherein the biotin-binding protein is non-covalently bound to a biotinylated tumor antigen.
Patented claim 17 recites, the pharmaceutical composition of claim 14, wherein the tumor antigen is derived from an ovarian cancer cell.
Claims of Patent 10800837 do not recite the pharmaceutical composition comprising an immunotherapy; however, this deficiency is made-up in the teachings of Chowdhury and Honjo.
Teachings of Chowdhury and Honjo are discussed above.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to generate and administer to a subject with cancer a therapeutically effective amount of a combination of the pharmaceutical composition of the patented claims and the anti-PD-1 antibody immunotherapy of Chowdhury and Honjo because Chowdhury and Honjo teach that PD-1 blockade could provide a boost to the natural immune response which when combined with cancer vaccines may be a reasonable approach for the treatment of less immunogenic tumors (Pg. 115 Column, first, Paragraph, third, Lines 3-7).
Response to Arguments
In the reply of 02/12/2026, Applicant cites the claims as amended are directed to a combination of the SAV and an immunotherapy. The '837 patent does not teach or suggest the combination of the SAV and an immunotherapy as presently claimed. For the reasons described above, Chowdhury does not remedy the deficiencies of the '837 patent. Therefore, the instant claims are non-obvious over the claims of the '837 patent.
Examiner’s Response: The arguments found in the Reply of 02/12/2026 have been carefully considered but are not deemed persuasive. This is because the Examiner maintains the rejection using the support as provided in the Response to Arguments given to the maintained 103 rejections on Pg 21-22 of the instant Office Action.
New Claim Objections
Claims 8 and 55 are objected to as being dependent on a rejected base claim (claim 1).
Allowable Subject Matter
Claims 8 and 55 are objected to as being dependent upon a rejected base claim (claim 1), but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642
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