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 .
The Amendments and Remarks filed 10/14/25 in response to the Office Action of 4/11/25 are acknowledged and have been entered.
Claims 70-72 have been added by Applicant.
Claims 1, 2, 4-7, 51-57, 59, 60, and 63-72 are pending.
Claims 1, 5, 51-56, and 66 have been amended by Applicant.
Claims 1, 2, 4-7, 51-57, 59, 60, and 63-72 are currently under examination.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Rejections Withdrawn
The rejection of claims 1, 2, 64, and 65 under 35 U.S.C. 102(a)(1) as being anticipated by Wu et al (Oncotarget, 2017, 8(20): 33024-33036) is withdrawn.
The rejection of claim(s) 1, 2, 64, and 65 under 35 U.S.C. 103 as being unpatentable over Wu et al (Oncotarget, 2017, 8(20): 33024-33036) in view of Lin et al (Immunol Res, 2010, 47: 86-112) is withdrawn.
Rejections Maintained
Claim Rejections - 35 USC § 102
Claim(s) 5-7 and 66 remain rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wu et al (Oncotarget, 2017, 8(20): 33024-33036).
Wu et al teaches a method of treating an HPV associated cancer comprising administering to a subject in need thereof a therapeutically effective amount of recombinant BAFF-E7, which is a therapeutically effective amount of a polynucleotide encoding BAFF fused to a therapeutically effective amount of the tumor specific antigen vaccine E7, wherein BAFF-E7 activates an immune response in a tumor, thereby treating cancer (see Abstract, Figures 2 and 5, and “Significant enchantment of systemic and tumor-infiltrated E7-specific CD8+ T-cell immune response was induced by chimeric BAFF-E7 vaccine” on page 33025, in particular). Wu et al further teaches BAFF of the BAFF-E7 construct functions as an adjuvant that stimulates T cell activation (Abstract and Figure 5B, in particular) and enhances the immunogenicity of the tumor antigen E7 as compared to the immunogenicity of the antigen alone (Figure 1, in particular). Wu et al further teaches previously studies administering BAFF resulted in CD4+ and CD8+ T-cell responses (right column on page 33024, in particular).
Regarding “increases B-cell expression of CD40 and/or CD86 as compared to a control” of claim 5, Wu et al does not measure expression of CD40 and/or CD86 by B cells or demonstrate BAFF increases B-cell expression of CD40 and/or CD86 as compared to a control. However, the claimed method appears the same absent a showing of obvious differences as the method of Wu et al administers all recited reagents of claims 5 and the instant specification discloses tumor antigens of the claimed invention include E6/E7 (page 18, in particular).
The examiner takes the position that administering BAFF-E7 of Wu et al co-administers BAFF and E7 as separate/distinct therapeutic agents fused together (Figure 6, in particular), wherein (i) the E7 of BAFF-E7 is a distinct/separate tumor vaccine antigen therapeutic agent and (ii) the BAFF of BAFF-E7 is a distinct/separate enhancer of an immune response (adjuvant) therapeutic agent (right column on page 33025, in particular).
Response to Arguments
In the Reply of 10/14/25, Applicant argues Wu et al does not teach co-administering BAFF and a tumor vaccine as separate entities wherein BAFF is administered as an adjuvant because Wu et al requires a BAFF-E7 fusion protein.
The amendments to the claims and the arguments found in the Reply of 10/14/25 have been carefully considered, but are not deemed persuasive. Regarding instant claims 5 and 66, the examiner takes the position that administering BAFF-E7 of Wu et al co-administers BAFF and E7 as separate/distinct therapeutic agents fused together (Figure 6, in particular), wherein (i) the E7 of BAFF-E7 is a tumor vaccine antigen therapeutic agent and (ii) the BAFF of BAFF-E7 is an enhancer of an immune response (adjuvant) therapeutic agent (right column on page 33025, in particular).
Claim Rejections - 35 USC § 103
Claim(s) 1, 2, 4-7, 51-56, 60, and 63-69 remain rejected under 35 U.S.C. 103 as being unpatentable over Wu et al (Oncotarget, 2017, 8(20): 33024-33036) as applied to claims 5-7 above, and further in view of Hamanishi et al (Int J Clin Oncol, 2016, 21: 462-473) and Freeman et al (US 2017/0247456 A1; 8/31/07).
Wu et al teaches a method of treating an HPV associated cancer comprising administering to a subject in need thereof a therapeutically effective amount of BAFF-E7 cancer vaccine, which is a therapeutically effective amount of a polynucleotide encoding BAFF fused to a therapeutically effective amount of the tumor specific antigen vaccine E7, wherein BAFF-E7 activates an immune response in a tumor, thereby treating cancer (see Abstract, Figures 2 and 5, and “Significant enchantment of systemic and tumor-infiltrated E7-specific CD8+ T-cell immune response was induced by chimeric BAFF-E7 vaccine” on page 33025, in particular). Wu et al further teaches BAFF of the BAFF-E7 construct functions as an adjuvant that stimulates T cell activation (Abstract and Figure 5B, in particular) and enhances the immunogenicity of the tumor antigen E7 as compared to the immunogenicity of the antigen alone (Figure 1, in particular). Wu et al further teaches previously studies administering BAFF resulted in CD4+ and CD8+ T-cell responses (right column on page 33024, in particular). Regarding instant claims 5 and 66, the examiner takes the position that administering BAFF-E7 of Wu et al co-administers BAFF and E7 as separate/distinct therapeutic agents fused together (Figure 6, in particular), wherein (i) the E7 of BAFF-E7 is a tumor vaccine antigen therapeutic agent and (ii) the BAFF of BAFF-E7 is an enhancer of an immune response (adjuvant) therapeutic agent (right column on page 33025, in particular).
Wu et al does not specifically teach administering BAFF-E7 as a polypeptide construct, administering a checkpoint inhibitor, or various recited activities that occur by administering BAFF. However, these deficiencies are made up in the teachings of Hamanishi et al and Freeman et al.
Hamanishi et al teaches PD-1 is mainly expressed on activated T cells, negatively regulating T cells’ antitumor effect, and PD-L1 is expressed on tumor cells (page 462, in particular). Hamanishi et al further teaches PD-L1 interacts with PD-1 to inhibit proliferation and cytokine production of T cells (in a natural immune-suppressive manner) and (“checkpoint”) inhibition of the interaction between PD-1 and PD-L1 by administered anti-PD-1 or anti-PD-L1 antibodies within the tumor microenvironment overcomes the natural immune-suppressive interaction of PD-1 and PD-L1 in the tumor microenvironment and enhances T cell response and mediates antitumor activity (page 462 and Figure 1, in particular). Hamanishi et al further teaches administering anti-PD-1 or anti-PD-L1 antibodies to a subject with cancer is therapeutically beneficial (pages 463-464, in particular).
Freeman et al teaches methods of treating cancer comprising administering a combination of a cancer vaccine and an anti-PD-1 antibody that is a checkpoint inhibitor that inhibits PD-1 ([0449] and [0483], in particular). Freeman et al further teaches said method wherein the cancer vaccine is a DNA-based vaccine or a peptide vaccine ([0483], in particular). Freeman et al teaches the anti-PD-1 antibody functions by enhancing, enhancing, or increasing immune responses ([0144], in particular). Freeman et al further teaches that administering an antigen in combination with an anti-PD-1 antibody enhances the immune response to the antigen ([0160], in particular) and that blockade of PD-1 can enhance an immune response to cancerous cells and result in antigen-specific immunity in a subject when administered with an antigen of interest ([0448] and [0451], in particular).
One of ordinary skill in the art would have been motivated, with an expectation of success, to perform a combined method to treat a subject with an HPV associated cancer comprising administering a combination of (i) the effective amount of BAFF-E7 cancer vaccine of Wu et al expressing an antigen of interest (E7) and (ii) an effective amount of anti-PD-1 antibody of Freeman et al because the cancer vaccine of Wu et al therapeutically treats cancer by activating an immune response, Freeman et al teaches methods of treating cancer comprising administering a combination of a cancer vaccine and the anti-PD-1 antibody, and blockade of PD-1 by the anti-PD-1 antibody of Freeman et al would predictably enhance the therapeutic immune response of Wu et al to tumor-specific antigen vaccine of Wu et al (E7) expressed by cancer cells because Freeman et al teaches blockade of PD-1 can enhance an immune response to cancerous cells and results in antigen-specific immunity in a subject when administered with an antigen of interest.
Regarding “increases B-cell expression of CD40 and/or CD86 as compared to a control” of claims 1 and 5, Wu et al does not measure expression of CD40 and/or CD86 by B cells or demonstrate BAFF increases B-cell expression of CD40 and/or CD86 as compared to a control. However, the claimed method appears the same absent a showing of obvious differences as the administered BAFF of Wu et al is indistinguishable from the BAFF recited by the claims.
In particular regards to claim 54, cited references do not demonstrate BAFF-treated B cells stimulate CD4+ T cell activity. However, the claimed method appears the same absent a showing of obvious differences as the combined method administers all recited reagents required to achieve the recited effect of claim 54. Further, as acknowledged by the instant specification, BAFF-treated B cells stimulate CD4+ T cell activity.
In particular regards to claim 55, cited references do not demonstrate BAFF reduces T regulatory cell activity and increases TH17 activity. However, the claimed method appears the same absent a showing of obvious differences as the combined method administers all recited reagents required to achieve the recited effect of claim 55.
Further, the examiner takes the position that BAFF increases “B-cell expression of CD40 and/or CD86 as compared to a control”, BAFF-treated B cells stimulate CD4+ T cell activity, and BAFF reduces T regulatory cell activity and increases TH17 activity, are not properties having significance greater than that of the expected property of a predicted therapeutic effect demonstrated by Wu et al of administering BAFF in the BAFF-E7 fusion construct of Wu et al. Therefore, recitation that BAFF increases “B-cell expression of CD40 and/or CD86 as compared to a control”, BAFF-treated B cells stimulate CD4+ T cell activity, and BAFF reduces T regulatory cell activity and increases TH17 activity are not sufficient to rebut obviousness of administering BAFF of the BAFF-E7 construct of Wu et al when administered BAFF-E7 of Wu et al has demonstrated to have the equal or greater property of expected therapeutic benefit. See MPEP 716.02(c). Further, see In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991), where the court held that the fact that another advantage would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.
Further, one of ordinary skill in the art would have been motivated, with an expectation of success, to perform the combined method wherein BAFF and E7 of BAFF-E7 are administered as polypeptide (as opposed to polynucleotide) because Freeman et al teaches methods of treating cancer comprising administering a combination of a cancer vaccine and an anti-PD-1 antibody that is a checkpoint inhibitor that inhibits PD-1 wherein the cancer vaccine is a DNA-based vaccine or a peptide vaccine, and substituting a BAFF and E7 polypeptide in place of a BAFF-E7 polynucleotide of the combined method is an example of a simple substitution of one known element for another to obtain predictable results because the translated polypeptide BAFF and E7 generated by the polynucleotide BAFF-E7 vaccine of Wu et al is what therapeutically functions in the method of Wu et al. The polynucleotide BAFF-E7 is used by Wu et al as a means of delivering a vehicle that generates the therapeutic BAFF and E7 polypeptide.
Further, one of ordinary skill in the art would have been motivated, with an expectation of success, to perform the combined method wherein anti-PD-L1 antibody is optionally administered in place of anti-PD-1 antibody because Hamanishi et al teaches both anti-PD-1 and anti-PD-L1 antibodies function by inhibiting the interaction between PD-1 and PD-L1 to overcome the natural immune-suppressive interaction of PD-1 and PD-L1 in the tumor microenvironment and enhance T cell response and mediates antitumor activity. Optionally substituting an anti-PD-L1 antibody in place of the anti-PD-1 antibody of the combined method is an example of a simple substitution of one known element for another to obtain predictable results because Hamanishi et al teaches both antibodies therapeutically function by inhibiting the interaction between PD-1 and PD-L1 to overcome the natural immune-suppressive interaction of PD-1 and PD-L1 in the tumor microenvironment.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 10/14/25, Applicant argues Wu et al teaches away from the claimed invention because Wu et al requires a BAFF-E7 fusion protein. Applicant further states claim 5 and claim 66 do not encompass a BAFF-E7 fusion protein because claims 5 and 66 have been amended to recite that BAFF and the tumor antigen (such as E7) are co-administered as separate therapeutic agents. Applicant further argues cited references do not measure expression of CD40 and/or CD86 by B cell following BAFF administration. Applicant further argues cited references do not demonstrate BAFF increases B-cell expression of CD40 and/or CD86 compared to a control. Applicant further argues the assertion that Applicant’s claimed method is the same as Wu et al is refuted by Wu et al by stating Wu et al is concerned with generating a CD8+ T cell response based on class I antigen presentation, which also fails induce any B-cell responses. Applicant further argues the combination of cited references do not teach or suggest co-administration of BAFF as an adjuvant.
The amendments to the claims and the arguments found in the Reply of 10/14/25 have been carefully considered, but are not deemed persuasive. In regards to the argument Wu et al teaches away from the claimed invention because Wu et al requires a BAFF-E7 fusion protein, the examiner disagrees. The claims encompass methods of administering BAFF as part of a fusion.
In regards the statement that claims 5 and 66 do not encompass a BAFF-E7 fusion protein because claims 5 and 66 have been amended to recite that BAFF and the tumor antigen (such as E7) are co-administered as separate therapeutic agents, the examiner disagrees. Regarding instant claims 5 and 66, the examiner takes the position that administering BAFF-E7 of Wu et al co-administers BAFF and E7 as separate/distinct therapeutic agents fused together (Figure 6, in particular), wherein (i) the E7 of BAFF-E7 is a tumor vaccine antigen therapeutic agent and (ii) the BAFF of BAFF-E7 is an enhancer of an immune response (adjuvant) therapeutic agent (right column on page 33025, in particular).
In regards to the argument cited references do not measure expression of CD40 and/or CD86 by B cell following BAFF administration, the examiner agrees. However, the claims do not require a step of measuring expression of CD40 and/or CD86.
In regards to the argument that cited references do not teach, suggest, or demonstrate BAFF increases B-cell expression of CD40 and/or CD86 compared to a control, the examiner agrees. However, as evidenced by Figure 2 of the instant specification, BAFF increases B-cell expression of CD40 and/or CD86 compared to a control. Therefore, the ability of BAFF to increase B-cell expression of CD40 and/or CD86 compared to a control is inherent. Further, the examiner takes the position that BAFF increases “B-cell expression of CD40 and/or CD86 as compared to a control” is not a property having significance greater than that of the expected property of a predicted therapeutic effect demonstrated by Wu et al of administering BAFF in the BAFF-E7 fusion construct of Wu et al. Therefore, recitation that BAFF increases “B-cell expression of CD40 and/or CD86 as compared to a control” is not sufficient to rebut obviousness of administering BAFF of the BAFF-E7 construct of Wu et al when administered BAFF-E7 of Wu et al has demonstrated to have the equal or greater property of expected therapeutic benefit. See MPEP 716.02(c). Further, see In re Baxter Travenol Labs., 952 F.2d 388, 21 USPQ2d 1281 (Fed. Cir. 1991), where the court held that the fact that another advantage would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.
In regards to the argument that the assertion that Applicant’s claimed method is the same as Wu et al is refuted by Wu et al by stating Wu et al is concerned with generating a CD8+ T cell response based on class I antigen presentation, which also fails induce any B-cell responses, this is not an anticipation rejection. Regarding “fails induced any B-cell response”, Wu et al teaches both wild-type and B cell deficient mice administered BAFF-E7 show significantly increased frequencies of E7-specific CD8+/IFN-g+ double-positive T cells (Figure 3), demonstrating a CTL-specific response generated by BAFF-E7 can occur in the absence of B cells. However, such a teaching does not demonstrate BAFF-E7 does not increase B-cell expression of CD40 and/or CD86 as compared to a control or any failure to induce any B-cell response in wild-type mice.
In particular regards to the argument the combination of cited references do not teach or suggest co-administration of BAFF as an adjuvant, the examiner disagrees. Wu et al teaches co-administering BAFF and E7 as a BAFF-E7 construct, wherein BAFF functions as an adjuvant.
Claim Rejections - 35 USC § 103
Claim(s) 5-7, 59, and 66 remain rejected under 35 U.S.C. 103 as being unpatentable over Wu et al (Oncotarget, 2017, 8(20): 33024-33036) as applied to claims 5-7 and 66 above, and further in view of Lin et al (Immunol Res, 2010, 47: 86-112).
Wu et al does not specifically teach administering tumor antigens other than E7. However, these deficiencies are made up in the teachings of Lin et al.
Lin et al teaches HPV E6 and E7 as “ideal targets for HPV vaccination” due to properties that include: HPV E6 and E7 are tumor-specific antigens that are present only on tumor cells and not on normal cells, HPV E6 and E7 would not raise issues of immune tolerance because they are completely foreign proteins, there is no risk of autoimmunity because HPV E6 and E7 are not self-proteins, and HPV E6 and E7 are constitutively expressed in malignant cells (page 89, in particular).
One of ordinary skill in the art would have been motivated, with an expectation of success, to treat HPV associated cancer by performing the method of treating HPV associated cancer of Wu et al wherein E6 is substituted in place of E7 of the BAFF-E7 construct of Wu et al because Lin et al teaches both E6 and E7 as “ideal targets for HPV vaccination”. This is an example of a simple substitution of one known element (E6) for another (E7) in order to obtain predictable results (target HPV associated cancer). Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 10/14/25, Applicant repeats arguments addressed above.
Claim Rejections - 35 USC § 103
Claim(s) 1, 2, 4-7, 51-57, 59, 60, and 63-69 remain rejected under 35 U.S.C. 103 as being unpatentable over Wu et al (Oncotarget, 2017, 8(20): 33024-33036) in view of Hamanishi et al (Int J Clin Oncol, 2016, 21: 462-473) and Freeman et al (US 2017/0247456 A1; 8/31/07) as applied to claims 1, 2, 4-7, 51-56, 60, and 63-69 above, and further in view of Lin et al (Immunol Res, 2010, 47: 86-112).
Teachings of Wu et al, Hamanishi et al, and Freeman et al are discussed above.
Wu et al, Hamanishi et al, and Freeman et al do not specifically teach administering tumor antigens other than E7. However, these deficiencies are made up in the teachings of Lin et al.
Lin et al teaches HPV E6 and E7 as “ideal targets for HPV vaccination” due to properties that include: HPV E6 and E7 are tumor-specific antigens that are present only on tumor cells and not on normal cells, HPV E6 and E7 would not raise issues of immune tolerance because they are completely foreign proteins, there is no risk of autoimmunity because HPV E6 and E7 are not self-proteins, and HPV E6 and E7 are constitutively expressed in malignant cells (page 89, in particular).
One of ordinary skill in the art would have been motivated, with an expectation of success, to treat HPV associated cancer by performing the combined method of treating HPV associated cancer of Wu et al, Hamanishi et al, and Freeman et al wherein E6 is substituted in place of E7 of the BAFF-E7 construct of Wu et al because Lin et al teaches both E6 and E7 as “ideal targets for HPV vaccination”. This is an example of a simple substitution of one known element (E6) for another (E7) in order to obtain predictable results (target HPV associated cancer). Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Response to Arguments
In the Reply of 10/14/25, Applicant repeats arguments addressed above.
Allowable Subject Matter
Claim 70 is allowed.
Claims 71-72 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
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.
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/SEAN E AEDER/Primary Examiner, Art Unit 1642