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 .
Claims Status
Claims 209-230 and 232-234 are pending in the application. Claim 231 is cancelled in the amendment filed 8/27/25.
Any objections and/or rejections from previous office actions that have not been reiterated in this office action are obviated.
Response to Arguments
Applicant's arguments filed 8/27/25 have been fully considered but they are not persuasive.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 209-230 and 232-234 is/are rejected under 35 U.S.C. 103 as being unpatentable over
Kobayashi et al. (US8,524,239B2) in view of Topalian et al. (New Engl. J. Med. 2012, 366, 2443-2454) and Norde, Wieger J., Frans Maas, Willemijn Hobo, Alan Korman, Michael Quigley, Michel GD, Konnie Hebeda Kester et al. "4 PD." Novel immunotherapeutic strategies after stem cell transplantation 71 (2013): 87 and in further view of Jain et al. (US 2013/0287688A1) as stated in the office action mailed 3/19/25.
Applicant asserts that Kobayashi et al. is different from the current claims at least in that Kobayashi et al. does not teach a phototoxic conjugate comprising at least one silicon phthalocyanine dye conjugated to a targeting molecule that binds PD-L1 as presently claimed. Kobayashi et al. does not recite a targeting molecule that binds PD-L1 at all. In addition, Kobayashi et al. also is silent as to uses of the phototoxic conjugate for killing an immune cell to inhibit immune suppression in a subject for treating a cancer. Kobayashi et al. does not mention inhibiting immune suppression by cells, nor immunosuppression at all, so Kobayashi et al. cannot teach or suggest that a phototoxic conjugate comprising a targeting molecule that binds PD-L1 would be used to target and kill immunosuppressive cells.
The reference of Kobayashi et al. was not used to teach of a targeting molecule that binds PD-L1 conjugated to at least one silicon phthalocyanine dye but was used to teach of antibody-IR700 molecule compositions wherein the IR700 is a silicon phthalocyanine dye conjugated to the antibody targeting molecule.
Although Kobayashi et al. exemplifies Panitumumab, Trastuzumab and HuJ591 antibodies, Kobayashi et al. states that an antibody is one that specifically binds to a cell surface protein and that the antibodies include intact immunoglobulins and the variants and portions of antibodies well known in the art that specifically binds to a surface protein on a cancer cell (e.g. lung (non-small cell carcinoma), melanoma, colorectal, etc.). One skilled in the art will recognize that because cell surface protein sequences are publicly available, that making or purchasing antibodies (or other small molecules that can be conjugated to IR700) specific for proteins is routine.
Kobayashi et al. further teaches that based on the similarity of the phototoxicity induced with three different MAbs against several different cells expressing a number of respective target molecules (antigens) and considering the potentially additive benefits from immunotherapy this method can be generally applicable to other mAbs. Therefore, Kobayashi et al. envisioned the use of other antibodies (or small molecules) for conjugating to IR700.
The reference of Topalian et al. was used to teach of the antitumor activity and safety of an anti-PD-L1 antibody (BMS-936558 (Nivolumab)) used to inhibit PD-1 and enhance T-cell response and thus mediate preclinical antitumor activity for treatment of patients with non-small lung cancer, melanoma, or renal-cell cancer.
The reference of Norde was also used to teach that BMS-936558 (Nivolumab) is used for the treatment of tumors by inhibiting T cells and may be conjugated to a fluorochrome moiety.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the panitumumab, Trastuzumab and HuJ591 antibodies of Kobayashi et al. for the anti-PD-1 antibody BMS-936558 of Topalian et al. as it provides the advantage of site specific targeting to cancer cells expressing PD-1 in combination with restoring T cell antitumor immunity.
It would have been predictable to one of ordinary skill in the art to substitute one known antibody for another known antibody as Kobayashi et al. teaches that the method can be generally applicable to other mAbs that target antibodies specific for cell surface receptors and the single BMS-936-559-IR700 compound allows the advantage of site specific delivery to lung (non-small cell carcinoma), melanoma, colorectal cancer cells.
The antibody-IR700 molecule compositions of Kobayashi et al. are used for the method of killing
tumor cells via PIT irradiation at a wavelength of 660 to 740 nm at a dose of at least 1 J cm-2, at least 10 J cm-2, at least 50 J cm -2, etc. that is an analogous method of treating a tumor of the instant claims as they have analogous steps. Therefore, the instant claims do not include any different method steps, any different conditions or any different imaging techniques to explain the observed results of the invention.
Applicant asserts that the other cited references, singly or in combination with Kobayashi et al., also fail to provide any motivation that would have led a person of skill in the art (POSITA) to have modified Kobayashi et al. in a manner to have arrived at the subject matter of the present claims. Kobayashi et al. is concerned with targeting tumor cells. One of ordinary skill in the art would not select the phototoxic conjugate of Kobayashi et al. for also targeting and killing immunosuppressive cells, when Kobayashi et al. does not say anything about targeting immune cells, such as immunosuppressive cells at all. Thus, there is no motivation to modify the phototoxic conjugate of Kobayashi et al. with a different targeting molecule, such as an anti-PD-L1 targeting molecule, and then also use it for targeting and killing immune cells to inhibit immune suppression.
The reference of Kobayashi et al. was used to teach antibody-IR700 molecule compositions as well as that stated above.
The reference of Topalian et al. teaches that stated above.
The reference of Norde teaches that stated above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the panitumumab, Trastuzumab and HuJ591 antibodies of Kobayashi et al. for the anti-PD-1 antibody BMS-936558 of Topalian et al. as it provides the advantage of site specific targeting to cancer cells expressing PD-1 in combination with restoring T cell antitumor immunity.
It would have been predictable to one of ordinary skill in the art to substitute one known antibody for another known antibody as Kobayashi et al. teaches that the method can be generally applicable to other mAbs that target antibodies specific for cell surface receptor and the single BMS-936-559-IR700 compound allows the advantage of site specific delivery to lung (non-small cell carcinoma), melanoma, colorectal cancer cells.
The reference of Kobayashi teaches that the method of killing tumor cells is due to the site specific selectivity of an antibody-IR700 conjugate as the unbound conjugates do not contribute to phototoxicity.
Therefore, the choice of antibody is unimportant to the phototoxicity but is important to the site specificity of the desired treatment that allows for effective PIT.
Applicant asserts that Topalian et al. is a study of the response of patients with advanced melanoma, non-small- cell lung cancer, castration-resistant prostate cancer, or renal-cell or colorectal cancer to treatment with an anti-PD-1 antibody. Topalian et al. suggest that PD-L1 expression in tumors is a candidate molecular marker for selecting patients for immunotherapy with an anti-PD-1 antibody and that no subjects with PD-L1-negative tumors had an objective response to treatment with the anti-PD-1 antibody (which is not a phototoxic conjugate). With respect to PD-L1, Topalian et al. teaches that it may be a molecular marker that warrants further exploration for use in selecting patients for immunotherapy with an anti-PD-1 antibody. In other words, the teachings of Topalian et al. suggest targeting PD-1 and not PD-L1 as presently claimed. Moreover, Topalian et al. relates to an entirely different mechanism, namely a blockade of PD-1, i.e. inhibiting this target and its pathway. Topalian et al. does not teach or suggest a mechanism by directing a conjugate to directly kill immune cells, or to directly kill immune cells expressing PD-L1.
The reference of Topalian et al. was not used teach of a mechanism by directing a conjugate to directly kill immune cells, or to directly kill immune cells expressing PD-L1.
The reference of Topalian et al. was used to teach of the antitumor activity and safety of an anti-PD-L1 antibody BMS-936558 (Nivolumab) used to inhibit PD-1 and enhance T-cell response and thus
mediate preclinical antitumor activity for treatment of patients with non-small lung cancer, melanoma,
or renal-cell cancer.
Applicant asserts that nowhere does Topalian et al. teach using an anti PD-L1 antibody as a targeting molecule to directly kill immune cells, nor any suggestion of using it as a phototoxic conjugate. Applicant submits that these teachings, including the passages cited by the Examiner, are not relevant to the presently claimed conjugate and would not lead one of ordinary skill in the art to the presently claimed conjugate, which is a conjugate of a silicon phthalocyanine dye conjugated to a targeting molecule that binds PD-L1. Topalian et al. (a) fails to even mention administration of a targeting molecule that binds PD-L1 or any PD-L1 antibodies, (b) fails to provide any motivation to modify the phototoxic conjugate of Kobayashi et al. with the addition of a targeting molecule that neither Topalian et al. or Kobayashi et al. teaches, and (c) fails to teach, suggest or provide any motivation that targeting immune cells with a phototoxic conjugate would have any efficacy as a treatment for a tumor.
The reference of Topalian et al. was not used to teach using an anti PD-L1 antibody as a targeting molecule to directly kill immune cells, nor any suggestion of using it as a phototoxic conjugate.
The reference of Topalian et al. was used to teach that stated above.
The reference of Kobayashi teaches that the method of killing tumor cells is due to the site specific selectivity of an antibody-IR700 conjugate as the unbound conjugates do not contribute to phototoxicity.
Therefore, the choice of antibody is unimportant to the phototoxicity but is important to the site specificity of the desired treatment that allows for effective PIT.
Applicant asserts that Norde et al. is alleged to teach fluorochrome-conjugated antibodies comprising anti-PD-L1 antibodies. Norde et al. uses of fluorochrome-conjugated antibodies, including a fluorochrome conjugated to anti-PD-L1 antibodies for labeling myeloid leukemia progenitor cells from leukemia samples and assessing expression by flow cytometry. Norde et al. simply teaches that a fluorochrome-conjugated PD-L1 antibody can be used to label PD-L1 positive cells. There is no teaching or suggestion in Norde et al. to use the fluorochrome-conjugated anti-PD-L1 antibody in a conjugate with at least one silicon phthalocyanine, nor that such a conjugate could be used for targeting the killing of immune cells, such as immunosuppressive cells, such as for eliminating PD- L1 expressing immune cells as described in the present application.
The reference of Norde was not used to teach of an anti-PD-L1 antibody conjugated to at least one silicon phthalocyanine for targeting or killing of immune cells, such as immunosuppressive cells, such as for eliminating PD-L1 expressing immune cells.
The reference of Norde was also used to teach that BMS-936558 (Nivolumab) is used for the treatment of tumors by inhibiting T cells and may be conjugated to a fluorochrome moiety as well as that stated above.
Applicant asserts that Jain et al. is directed to a method of improving the delivery or efficacy of a therapy in a subject, such as a cancer therapy, that involves administration of an anti-hypertensive and/or a collagen-modifying agent (AHCM; e.g., angiotensin II antagonist, such as losartan) in addition to the therapy (e.g., cancer therapy). Photodynamic therapy (PDT) and ipilimumab (an example of immunotherapy that blocks the protein CTLA-4) are individually mentioned only as examples of a cancer therapy, within a list of other cancer therapies including radiation and surgery, to be used in combination with the AHCM to improve the delivery or efficacy of the therapy. There is not even a teaching or suggestion of a combination therapy, combining a PDT agent as a conjugate with ipilimumab in the absence of the AHCM. As taught in Jain et al., the AHCM enhances the delivery or efficacy of the PDT or the immunotherapy (e.g., an immune checkpoint inhibitor). Thus, Jain et al. is focused on completely different combination therapy methods for a completely different purpose: specifically, the requirement for AHCM along with a second agent or therapy (either AHCM and a PDT agent, or AHCM and an immunotherapy agent). A skilled person would not even be motivated to combine the teachings of Jain et al. with Kobayashi et al. or the other cited references, as Jain et al. focuses on a separate problem, namely the delivery and uptake of drugs, specifically vascular transport throughout tissues and
transvascular transport into tissues after drug delivery through the administration of AHCM.
The reference of Jain et al. was used to teach that the combination of an anti-hypertensive agent in combination with the combination of various therapies (e.g. immunotherapy, photodynamic
therapy) to improve the delivery and efficacy of the PDT.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to combine immunotherapy and a phototoxic agent to predictably and effectively kill tumor cells and the BMS-936-559-IR700 compound predictably provides an improved delivery and efficacy of photoimmunotherapy.
Applicant asserts that the photodynamic therapy (PDT) taught in Jain et al. is completely different in the biological mechanism and immunological response associated with photoimmunotherapy (PIT) recited in the present claims. At a minimum, the PDT agents photosensitizing agents administered for the PDT are described by Jain et al. are naked photosensitizing agents and do not possess a targeting moiety. In stark contrast, in photoimmunotherapy (PIT), as claimed, the phototoxic silicon phthalocyanine dye is conjugated to a PD-L1 targeting molecule that results in targeting the conjugate, and the subsequent phototoxicity, to only specific target cells, including immunosuppressive cells. Thus, any teachings of Jain et al. related to PDT are not relevant or applicable to photoimmunotherapy methods, including those described in the instant application or in combination with Kobayashi et al.
The reference of Jain et al. was not used to teach of phototoxic silicon phthalocyanine dye is conjugated to a PD-L1 targeting molecule photoimmunotherapy methods but was used to teach that the combination of an anti-hypertensive agent in combination with the combination of various therapies (e.g. immunotherapy, photodynamic therapy) to improve the delivery and efficacy of the PDT.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date to combine immunotherapy and a phototoxic agent to predictably and effectively kill tumor cells and the BMS-936-559-IR700 compound predictably provides an improved delivery and efficacy of photoimmunotherapy.
Conclusion
No claims are allowed at this time.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MELISSA JEAN PERREIRA whose telephone number is (571)272-1354. The examiner can normally be reached M9-3, T9-3, W9-3, Th9-2, F9-2.
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Michael Hartley can be reached at 571-272-0616. The fax phone number for the organization where this
application or proceeding is assigned is 571-273-8300.
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/MELISSA J PERREIRA/Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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