DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant's reply filed on 10/15/2025 is acknowledged. Claims 1-20 are pending. Claims 10 and 19 are withdrawn. No claims are amended.
3. Claims 1-9, 11-18 and 20 are under examination.
Information Disclosure Statement
4. The information disclosure statement (IDS) submitted on 9/2/2025 has been considered by the examiner.
Rejections Maintained
Claim Rejections - 35 USC § 103
5. 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.
6. Claims 1-9, 12, 15-17 and 20 remain rejected under 35 U.S.C. 103 as being unpatentable over LaCelle et al. (US 2009/0317407A1, pub. date: 12/24/2009), in view of Bedi et al. (WO 2011/109789A2, pub. date: 9/9/2011, PTO 892 dated 4/22/2024), as evidenced by Sundar et al. (Ther Adv Med Oncol, 2015, 7(2):85-96, PTO 892 dated 4/22/2024).
Regarding claim 1, LaCelle et al. teaches a method of stimulating an immune response against a target antigen, and a method of treating at tumor in a subject, comprising: administering a therapeutically effective amount of an agent that significantly depletes the number of CD4+ T cells in the subject subsequent to the subject receiving a first dose of a therapeutically effective amount of an immunogenic composition comprising the target antigen, wherein the subject has a tumor comprising the target antigen; and administering a therapeutically effective amount of a second dose of the immunogenic composition to the subject, thereby stimulating an immune response against the target antigen,
wherein the agent that significantly depletes CD4+ T cells is an anti-CD4 antibody, wherein the agent that significantly depletes CD4+ T cells is administered at least 10 days subsequent to the subject receiving the first dose of the immunogenic composition (claims 1-6 and 18).
LaCelle teaches that the immunogenic composition comprises a tumor antigen, such as an antigen expressed by a tumor present in a subject (or which has been removed from the subject), is an autologous tumor vaccine, may further comprise immunostimulant such as GM-CSF ([0119]). At 10 days subsequent to the subject receiving the first dose of a therapeutically effective amount of the immunogenic composition comprising a target antigen of the tumor of the subject, the subject would have had the cancer for an amount of time long enough to prime the immune system, allowing formation of tumor-specific CD8+ lymphocytes including CD8+ memory cells.
Regarding claim 2, LaCelle et al. teaches that the tumor is a breast cancer, a melanoma, a lung cancer, a renal cell carcinoma, a prostate cancer, an ovarian cancer, a cervical cancer, a colon cancer, a liver cancer, or combinations thereof (claim 17).
Regarding claim 3, LaCelle et al. teaches that the subject is a human (claim 15).
Regarding claim 4, LaCelle et al. teaches that the anti-CD4 antibody is a monoclonal antibody ([0256]).
Regarding claim 5, LaCelle et al. teaches that the anti-CD4 antibody is a humanized monoclonal antibody or a human monoclonal antibody ([0319], [0256]).
Regarding claim 6, LaCelle et al. teaches that the anti-CD4 antibody is zanolimumab ([0255]).
Regarding claim 7, LaCelle et al. teaches that zanolimumab is administered at a dose of 0.1-5 mg/kg ([0320]). For an average body weight of 60 kg of adult human subjects, the dosages of zanolimumab would be 6 mg/day to 300 mg/day.
Regarding claim 8, LaCelle et al. teaches that zanolimumab is administered by i.v. ([0320]).
Regarding claim 15, the limitation “the administration of the anti-CD4 antibody induces IFN-[Symbol font/0x67] response in the subject” is considered an inherent property of zanolimumab.
Regarding claim 16, administering a therapeutically effective amount of an immunogenic composition to the subject meets the limitation “administering a therapeutically effective amount of an immune modulating agent to the subject”.
LaCelle et al. does not teach administering to the subject a therapeutically effective amount of an anti-PD-1 antibody such as nivolumab, wherein the anti-PD-1 antibody is administered intravenously. LaCelle et al does not teach further administering a cytotoxic anticancer agent, wherein the cytotoxic agent includes a chemotherapy molecule, or a kinase inhibitor
Regarding claims 1-3 and 9, Bedi et al teaches a method of treating a non-T cell malignancy which does not express CD4 on the tumor cell in a subject, the method comprising administering to the subject having a tumor an anti-CD4 antibody that targets and depletes CD4 regulatory T cells (Tregs) in combination with an immunostimulatory antibody that target PD1 (an anti-PD1 antibody) ([0142] and claims 62-66), wherein the cancer is prostate, pancreatic, biliary, colon, rectal, liver, kidney, lung, testicular, breast, ovarian, pancreatic, brain, and head and neck cancers, melanoma, ([0153]), the subject is human ([0154]), the anti-CD4 antibody is zanolimumab ([0163]), the anti-PD1 antibody is MDX-1106 ([0163]). MDX-1106 is a fully human antibody, also known as nivolumab, as evidenced by Sundar (page 87, column 1, para 3).
Regarding claim 12, Bedi et al. teaches that the administration can be intravenous administration ([0197]).
Regarding claims 16, 17 and 20, Bedi et al. teaches that the method further comprises administering a cytotoxic anticancer agent, wherein the cytotoxic agent includes a chemotherapy molecule, or a kinase inhibitor ([0141] and [0142] and claims 62-66).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of LaCelle to further treat the subject with an anti-PD-1 antibody in view of Bedi. One of ordinary skill in the art would have been motivated to do so because LaCelle et al. teaches treating cancers with an immunogenic composition and an anti-CD4 antibody, and Bedi et al. teaches treating same cancers with an anti-CD4 antibody and an anti-PD-1 antibody.
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960).
In the instant case, LaCelle et al. teaches treating cancers with an immunogenic composition and an anti-CD4 antibody. Bedi et al. teaches treating same cancers with an anti-CD4 antibody and an anti-PD-1 antibody. It is prima facie obvious to have treated cancers with a combination of an immunogenic composition, an anti-CD4 antibody and an anti-PD-1 antibody. One of ordinary skill in the art would have had a reasonable expectation of success because each subcombination has been used in the art for treating same cancers.
7. Claims 1-9, 11-17 and 20 remain rejected under 35 U.S.C. 103 as being unpatentable over LaCelle et al. (US 2009/0317407A1, pub. date: 12/24/2009), in view of Bedi et al. (WO 2011/109789A2, pub. date: 9/9/2011, PTO 892 dated 4/22/2024), as evidenced by Sundar et al. (Ther Adv Med Oncol, 2015, 7(2):85-96, PTO 892 dated 4/22/2024), further in view of Langermann (US 2010/0055102A1, pub. date: 3/4/2010, PTO 892 dated 4/22/2024).
The teachings of LaCelle et al. and Bedi et al. have been set forth above as they apply to claims 1-9, 12, 15-17 and 20.
Regarding claim 11, LaCelle et al. and Bedi do not teach the dose of the anti-PD-1 antibody.
Regarding claims 13-14, LaCelle and Bedi et al do not teach that the anti-CD4 antibody is administered concurrently with or before the administration of the anti-PD1 antibody.
Langermann teaches a method of treating cancer in a subject, comprising administering to said subject an effective treatment regimen comprising an anti-PD-1 antibody, and a potentiating agent such as cyclophosphamide, wherein cyclophosphamide depletes Treg cells (abstract, [0022], [0027], [0030], [0209]-[0212]), the subject is human ([0057]), the anti-PD-1 antibody and the potentiating agent can be combined with a tumor vaccine ([0237],and [0238]), the dosages of the anti-PD-1 antibody for a human subject are commonly in the range of 0.1-100 mg/kg daily ([0204], [0205]). For an average body weight of 60 kg of adult human subjects, the dosages include 6mg/day to 6000mg mg. Langermann teaches that B7-H1 (the predominant PD-1 ligand) is overexpressed in many cancers including melanoma ([0011] and [0012]). Langermann teaches that cyclophosphamide (which depletes Treg cells) is administered at same time or before administering of the anti-PD1 antibody ([0202] and [0217]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the dosages of anti-PD1 antibody taught by Langermann in the method of LaCelle and Bedi in view of Langermann. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Langermann teaches using anti-PD1 antibody at these dosage for treating human subjects having a cancer.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have administered anti-CD40 antibody at same time or before the administration of anti-PD1 antibody in view of Langermann. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Langermann teaches cyclophosphamide (which depletes Treg cells) can be administered at same time or before administering of the anti-PD1 antibody ([0202] and [0217]).
8. Claims 1-9, 12, 15-18 and 20 remain rejected under 35 U.S.C. 103 as being unpatentable over LaCelle et al. (US 2009/0317407A1, pub. date: 12/24/2009), in view of Bedi et al. (WO 2011/109789A2, pub. date: 9/9/2011, PTO 892 dated 4/22/2024), as evidenced by Sundar et al. (Ther Adv Med Oncol, 2015, 7(2):85-96, PTO 892 dated 4/22/2024), further in view of Kim et al. (US 2013/0028898A1, pub. date: 1/31/2013, earlier pub. date: 10/27/2011, PTO 892 dated 4/22/2024).
The teachings of LaCelle et al. and Bedi et al. have been set forth above as they apply to claims 1-9, 12, 15-17 and 20.
Regarding claim 18, LaCelle et al. and Bedi do not teach further administering an mTOR inhibitor such as rapamycin.
Kim et al. teaches a methods for treating cancer in subjects in need thereof comprising administering to the subjects an effective amount of an mTOR inhibitor and an effective amount of a CD4 lymphocyte depleting agent ([0011]), wherein the cancer is melanoma ([0026]), the subject is human ([0029]), the mTOR inhibitor is Temsirolimus (CCI-779), Evirolimus (RAD001) or Rapamycin ([0035]), the CD4 lymphocyte depleting agent is a humanized anti-CD4 antibody, zanolimumab, the dose of the antibody is 100-200mg/day to 1900-200mg/day ([0037], [0038], [0052]), the antibody can be administered intravenously ([0060]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of LaCelle and Bedi to further treat cancer with an mTOR inhibitor in view of Kim. One of ordinary skill in the art would have been motivated to do so because LaCelle and Bedi et al. teach that their method of treating cancer with an anti-CD40 antibody and an anti-PD1 antibody can further comprise administering another anticancer therapy ([0033]), and Kim et al. teaches treating cancer with an anti-CD40 antibody such as zanolimumab and an mTOR inhibitor. One of ordinary skill in the art would have had a reasonable expectation of success because each of the agents have been used in the art for treating same cancer.
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960).
Applicant’s Arguments
The response states that firstly, LaCelle et al. teaches a method that has a very different mechanism from the method disclosed in other references (e.g., Bedi et al.) or the method claimed in the present application. The method of LaCelle et al. is directed to enhancing immune response to cancer vaccine. Specifically, LaCelle et al. teaches "reducing the number of CD4+ T cells in a subject after the subject receives a first dose of an immunogenic composition that includes the target antigen (such as a cancer vaccine), wherein the subject has a tumor that expresses the target antigen." Abstract of LaCelle et al.; see also the claims of LaCelle et al. LaCelle's method is based on the discovery that a first dose of vaccine (an immunogenic composition) induces detrimental CD4+ Treg cells (see LaCelle, Example 1, para. [0139], Example 9, para. [0223]), and by reducing the detrimental CD4+ Treg cells, the second dose of cancer vaccine would induce stronger immune response (Id.).
On the other hand, the method of Bedi et al. is directed to cancer treatment using immune checkpoint inhibitors, such as PD-1 inhibitors. While cancer vaccine is used to prime the immune system to recognize and attack cancer cells, immune checkpoint inhibitor is used to unleash an existing but suppressed immune response. Given the nature of unpredictability in cancer treatment, a person skilled in the art would not have apply the teaching of LaCelle in particular, reducing the number of CD4+ T cells in a subject after the subject receives a first dose of an immunogenic composition to the method of Bedi with reasonable expectation of success. Although the Examiner cited In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980), and In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960), asserting that technical solutions having the same purpose may be combined, the applicant respectfully disagrees. The applicant submits that, unlike other technical fields, the pharmaceutical field is characterized by a high degree of unpredictability. It is well known to a person skilled in the art that combination therapies involving different primary drugs have entirely different mechanisms of action, and therapies with different mechanisms cannot be simply combined. The applicant notes that the case law cited by the Examiner pertains to the field of detergents, which is far more predictable than the pharmaceutical field. Therefore, the applicant submits that the conclusions of these precedents are not directly applicable to the present case.
More importantly, none of the cited references, including LaCelle et al., teaches the limitation "wherein the subject has had the cancer for an amount of time long enough to prime the immune system prior to administration of the anti-CD4 antibody, allowing formation of tumor-specific CD8+ lymphocytes, including CD8+ memory cells" as recited in the claimed method.
The examiner alleged that "LaCelle et al. teaches that the immunogenic composition comprises a tumor antigen, such as an antigen expressed by a tumor present in a subject (or which has been removed from the subject), is an autologous tumor vaccine, may further comprise immunostimulant such as GM-CSF ([0119]). At 10 days subsequent to the subject receiving the first dose of a therapeutically effective amount of the immunogenic composition comprising a target antigen of the tumor of the subject, the subject would have had the cancer for an amount of time long enough to prime the immune system, allowing formation of tumor-3 specific CD8+ lymphocytes including CD8+ memory cells." (Office Action, bridging paragraph at page 3-4).
However, LaCelle et al. does not explicitly teach that at 10 days subsequent to the subject receiving the first dose of a therapeutically effective amount of the immunogenic composition, the cancer in the subject would prime the immune system to allow formation of tumor-specific CD8+ lymphocytes including CD8+ memory cells.
As discussed above, LaCelle's method is based on the discovery that a first dose of vaccine induces detrimental CD4+ Treg cells (see LaCelle, Example 1, para. [0139], Example 9, para. [0223]), and by reducing the detrimental CD4+ Treg cells, the second dose of cancer vaccine would induce stronger immune response (Id.). Therefore, the purpose of using a first dose of an immunogenic composition in LaCelle is not to allow formation of tumor-specific CD8+ lymphocytes including CD8+ memory cells. Therefore, LaCelle does not teach the limitation "wherein the subject has had the cancer for an amount of time long enough to prime the immune system prior to administration of the anti-CD4 antibody, allowing formation of tumor-specific CD8+ lymphocytes, including CD8+ memory cells," either explicitly or implicitly/inherently.
The method of LaCelle uses two doses of cancer vaccine regime wherein the CD4+ T cells in the subject are reduced subsequent to the first dose of cancer vaccine. The method of Bedi et al. does not involve cancer vaccine. Therefore, even assuming that a person skilled in the art was motivated to combine LaCelle and Bedi which the applicant respectfully disagree the person would have only used a cancer vaccine to induce CD4+ Treg cells followed by the reduction/depletion of the CD4+ Treg cells, but not applying the method of reducing/depleting CD4+ Treg cells to a subject that has had the cancer for an amount of time long enough to prime the immune system prior to administration of the anti-CD4 antibody, allowing formation of tumor-specific CD8+ lymphocytes, including CD8+ memory cells.
For at least the foregoing reasons, the applicant respectfully submits that the claimed methods are not obvious over LaCelle in view of Bedi and other cited references.
Response to Arguments
Applicant’s arguments that LaCelle et al. teaches a method that has a very different mechanism from the method disclosed in other references (e.g., Bedi et al.) or the method claimed in the present application have been carefully considered but are not persuasive. LaCelle et al. teaches treating cancer with an immunogenic composition (vaccine) and an anti-CD4 antibody, wherein the anti-CD4 antibody is used to deplete tumor-induced regulatory T cells (Treg cells, CD4+CD25+ T cells) ([0012], [0037]). Bedi et al. teaches treating same cancer with an anti-CD4 antibody in combination with an immunostimulatory antibody that target PD1 (an anti-PD1 antibody or anti-PD-L1 antibody) ([0142], claims 62-66, and [0153]). The anti-CD4 antibody is also used to deplete CD4+ Treg cells ([0206]). The anti-PD-1 antibody or anti-PD-L1 antibody is used to stimulate T cell activity (enhance immune response), which is also required by tumor vaccine. Bedi teaches that their method can further comprise administering a cancer vaccine (claim 58). It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of LaCelle to further treat the subject with an anti-PD-1 antibody in view of Bedi because Bedi teaches that the anti-PD-1 antibody stimulates T cell response. One of ordinary skill in the art would have been motivated to do so because Bedi et al. teaches treating same cancer with an anti-CD4 antibody in combination with an immunostimulatory antibody that target PD1 (an anti-PD1 antibody or anti-PD-L1 antibody) ([0142], claims 62-66, and [0153]), and a cancer vaccine (claim 58).
Applicant’s arguments that the case law cited by the Examiner pertains to the field of detergents, which is far more predictable than the pharmaceutical field are not persuasive. In the instant case, LaCelle et al. teaches treating cancer with an immunogenic composition (tumor vaccine) and an anti-CD4 antibody. Bedi et al. teaches treating same cancer with an anti-CD4 antibody, an anti-PD-1 antibody, and a vaccine. It would have been prima facie obvious to treat cancer with a combination of an immunogenic composition, an anti-CD4 antibody and an anti-PD-1 antibody. One of ordinary skill in the art would have had a reasonable expectation of success because each subcombination (vaccine + anti-CD4 antibody, anti-PD-4 antibody + anti-PD-1 antibody + vaccine) has been used in the art for treating same cancers.
Applicant’s arguments of no teaching of formation of CD8+ memory cels are not persuasive. LaCelle et al. teaches that the agent that significantly depletes CD4+ T cells (e.g. anti-CD4 antibody) is administered at least 10 days, at least 14 days, 30 days, at least 60 days subsequent to the subject receiving the first dose of the immunogenic composition ([0111]). LaCelle teaches that the immunogenic composition comprises a tumor antigen, such as an antigen expressed by a tumor present in a subject (or which has been removed from the subject), is an autologous tumor vaccine ([0119]). At 10 days, 14 days, 30 days or 60 days subsequent to the subject receiving the first dose of a therapeutically effective amount of the immunogenic composition comprising a target antigen of the tumor of the subject, the subject would have had the cancer for an amount of time long enough to prime the immune system, allowing formation of tumor-specific CD8+ lymphocytes including CD8+ memory cells. It is well-known in the art that CD8+ memory T cells begin to form around 1 to 2 weeks after initial vaccination.
For the foregoing reasons, the rejections are deemed proper and are therefore maintained.
9. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Goding et al. Restoring immune function of tumor-specific CD4+ T cells during recurrence of melanoma, J Immunol. 2013 May 1; 190(9): 4899–4909 (cited in “The Notice of Reasons for Rejection for the counterpart Japanese patent application 2023-126665, mailed on June 2, 2025 which is cited in the IDS filed on 9/2/2025).
Goding teaches that while blockade of the PD-1/PD-L1 pathway with anti-PD-L1 antibodies or depletion of tumor-specific Treg cells alone failed to reverse tumor recurrence, combination of PD-L1 blockade with tumor-specific Treg cell depletion effectively mediated disease regression (abstract).
Conclusion
10. No claims are allowed.
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.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to HONG SANG whose telephone number is (571)272-8145. The examiner can normally be reached Monday-Friday 8am-5pm.
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/HONG SANG/Primary Examiner, Art Unit 1643
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