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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 3/4/26 has been entered.
Claims and Previous Objections/Rejections Status
Claims 209-230 and 232-234 are pending in the application.
Any objections and/or rejections from previous office actions that have not been reiterated in this office action are obviated.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 209-230 and 232-234 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
Claims 209-230 and 232-234 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The disclosure does not describe “main monomer component greater than 90% of the conjugate in the composition. The Table 10 of the disclosure does describe specific % monomer percentages but does not describe the range of all monomer percentages greater than 90%.
The disclosure does not describe a representative number of examples of the combinations of silicon phthalocyanine dyes and PD-L1 targeting molecules and/or all necessary conditions that provide a main monomer component in greater than 90% of the conjugate in the composition.
The dependent claims fall therewith.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 209-230 and 232-234 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph.
Claims 209-230 and 232-234 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. The recitation of “main monomer component” is unclear and confusing as this statement is drawn to the silicon phthalocyanine-PD-L1 conjugate that does not exclude any aggregates wherein aggregates have a main monomer component. The silicon phthalocyanine-PD-L1 conjugate may also comprise more than one silicon phthalocyanine dye. The recitation of “main monomer component” is functional language and therefore, the same components will be expected to have the same functions under specific analogous conditions.
The dependent claims fall therewith.
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 Nakajima et al. (BMC Cancer 2014, 14:389; pp1-7), Brahmer et al. (New Engl. J. Med. 2012, 366, 2455-2456), 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.
Kobayashi et al. (US 8,524,239B2) discloses antibody-IR700 molecules and the method of treatment of a cell or tissue with the antibody-IR700 molecules (abstract; column 1, lines 55+; column 8, lines 4-9) wherein the antibody binds to a cell surface protein for selective killing of tumor cells (column 17, lines 25-33).
The IR700 dye encompasses the silicon phthalocyanine dye IR700 of the instant claims
212,213,232.
The antibodies selectively bind to cell surface protein expressed on tumor cells and comprise anti-CTLA-4, panitumumab, Trastuzumab and HuJ591 (column 1, lines 64+; column 18, lines 24-36; column 26, lines 50-55).
The antibody-IR700 molecule is prepared as a pharmaceutical composition comprising a
pharmaceutically acceptable carrier (column 9, lines 47+) that encompasses the phototoxic
pharmaceutical composition comprising a pharmaceutical carrier of the instant claim 214.
The antibody-IR700 molecules contained no detectable aggregates as determined by HPLC (column 27, lines 54-60).
The antibody-IR700 molecules are used for killing a target cell, such as a tumor cell (column 1, lines 55+; column 2, lines 4-10) that encompasses the tumor cell of the instant claim 230.
The method includes administering the antibody-IR700 molecule to a subject intravenously, injection, etc. and irradiating the subject, such as irradiating the tumor in a subject (column 2, lines 12- 20; column 12, lines 22-31; column 13, lines 55-65; column 22, lines 8-21) that encompasses administration intravenously or as an injection of the instant claim 224.
The suitable dose of irradiation following administration of the antibody-IR700 molecule is at least 1 J cm-2 at a wavelength of 660-740 nm (for example at a wavelength of about 680 nm), at least 10 J cm-2, at least 50 J cm -2, etc. (column 8, lines 55+; column 1, lines 67-column 2, lines 1-3; column 12, lines 4-17) that encompasses irradiating the lesion at a wavelength of 690 ± 50 nm at a dose of at or about 50 J cm -2 of the instant claims 219,223 or at a wavelength of 690 ± 20 nm of the instant claim 222.
The antibody-IR700 molecules reduce or decrease the viability of cells to which it binds and decrease the size of a tumor via PIT (abstract; column 8, lines 55; column 10, lines 56+; column 11, lines 5-15) that encompasses the phototoxicity inhibits the growth of a tumor of the instant claim 218.
The tumors include bladder, stomach, head or neck, breast, lung, colorectal, etc. (column 18, lines 37+; claims 13,18,21) that encompass the diseases or conditions of the instant claim 228, such as bladder cancer, breast cancer, stomach cancer, lung, colon, etc.
Kobayashi further discloses that twenty-four hours after administration of antibody-IR700, in
mice receiving PIT was irradiated (dose level 50 J cm-2) (column 30, lines 66+; column 31, lines 1-2) that encompasses that the irradiation is carried out between 30 minutes and 96 hours or 24 hours ± hours after administering the phototoxic conjugate of the instant claims 220 and 221, respectively.
The patient may be administered one or more antibody-IR700 molecules, repeatedly over a period of time (such as bi-weekly or monthly, etc.) (column 23, lines 1-3; column 25, lines 18-28).
Multiple irradiations may be performed, such as 2,3,4,4,5,6,7,8,9 or 10 separate
administrations on the same day, on successive days, or every 1-3 days, every 2-3 weeks, etc. (column 12, lines 17-21; column 23, lines 11-19). Repeated PIT and multiple doses of antibody controlled tumor regrowth are used for long term management of cancer patients and resulted in tumor free survival for more than 4 months (column 15, lines 38+) that encompasses the repeated administration of the antibody-IR700 molecules and the dosing schedule whereby steps are repeated, such as about 2 weeks, 3 weeks, etc. of the instant claims 225 and 226.
The NIR irradiation light is administered by using a fiber-coupled laser diodes with diffuser tips (column 16, lines 9-17) that encompass the cylindrical diffusing fibers of the instant claim 227.
Kobayashi et al. does not disclose a targeting molecule that binds PD-L1, such as those of the instant claims 210,211,233 and 234 or that the immune cell is a T-cell of the instant claim 216.
Kobayashi et al. further discloses that it that antibody-based photosensitizers (such as mAb-
based photosensitizers) are activated by light for targeted photoimmunotherapy (PIT) only when bound to the target molecule on the cancer cellular membrane. The fluorophore IR700 can become a photosensitizer when conjugated to an antibody specific for cell surface receptor and can thus be used for target specific photodynamic therapy of undesired cells, such as tumors or cancer cells. Considering the potentially additive benefits from immunotherapy this method can be generally applicable to other mAbs (column 14, lines 29-46).
Nakajima et al. (BMC Cancer 2014, 14:389; pp1-7) discloses that photoimmunotherapy (PIT) is a highly cell-selective cancer therapy, which utilizes a monoclonal antibody (mAb) conjugated to the photosensitizing phthalocyanine dye, IRDye700DX (IR700). After intravenous injection, mAb-IR700 conjugates preferentially to cancer cells expressing the proper antigen and subsequent exposure of the cells to near infrared (NIR) light induces highly selective and rapid cell necrosis. An attractive feature of PIT is that minimal damage is seen in adjacent normal cells. The effectiveness of PIT appears generalizable across a number of different types of cancers and with multiple mAb-IR700 conjugates. When the mAb-IR700 conjugate is well matched to the target tumor, exposure to NIR light results in rapid and severe damage to the cell membrane inducing necrotic cell death within a minute (p1, Background).
Brahmer et al. (New Engl. J. Med. 2012, 366, 2455-2456) discloses the intravenous administration of anti-PD-L1 antibody to patients with selected advanced cancers, such as colorectal, non-small-cell lung cancer, etc. (abstract; p2456, Study Design; p2457, Study Treatment and Safety Evaluation).
The anti-PD-L1 antibody is T-cell modulating and comprises BMS-936559 (p2456, left column,
last paragraph; p2456, right column, last paragraph).
PD-L1 is selectively expressed on many tumors (p2456, left column, third paragraph) and the antibody-mediated blockade of PD-L1 induced durable tumor regression (abstract).
The anti-PD-L1 antibody blocks interactions between PD-L1 and both PD-1 and CD80; the latter interaction has been shown to down-modulate T-cell responses in vitro and in vivo (p2463, left column, last paragraph).
Brahmer et al. further teaches that anti-CTLA-4 antibody was approved for the treatment of patients with stage IV melanoma (p2456, left column, second paragraph).
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 discloses fluorochrome-conjugated antibodies comprising anti-PD-L1 antibodies (p90, right column, Flowcytometry).
Antibodies, such as BMS-936-559 (MDX-1105) has been evaluated in clinical trials for tumor treatments (p90, right column, second paragraph; p90, right column, Flowcytometry).
PD-L1 molecules bind CD80 which results in T cell inhibition (p89, right column, last paragraph). PD-1 signaling pathway suppresses MiHA-specific CD8+ T cell responses and PD-1 blockade may be an attractive approach to boost GVT immunity in patients with persistent or relapsed disease (p90, left column, first paragraph).
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 anti-CTLA-4, panitumumab, Trastuzumab and HuJ591 antibodies of Kobayashi et al. for the anti-PD-L1 antibody BMS-936559 (MDX-1105) of Brahmer et al. as Nakajima et al. teaches that PIT is a highly cell-selective cancer therapy, which utilizes a monoclonal antibody (mAb) conjugated to the photosensitizing phthalocyanine dye, IRDye700DX (IR700) conjugates preferentially to cancer cells expressing the proper antigen and that the BMS-936559-mediated blockade of PD-L1 induced durable tumor regression and provides the advantage of site specific binding of BMS-936559-IR700 to specific tumor cells that allows for the targeted PIT of tumors, such as lung, colon, etc. with a reasonable expectation of success.
It would have been predictable to one of ordinary skill in the art to substitute one known site specific targeted antibody for another known site specific targeted antibody as Nakajima et al. teaches that the various mAbs are conjugated to IR700 and are chosen to selectively target specific cancer cells expressing the proper antigen and Kobayashi et al. teaches that the method can be generally applicable to other mAbs that target antibodies specific for cell surface receptors.
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 for PIT-mediated killing of tumor cells, such as lung, colon, head or neck, bladder, etc.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention that BMS-936559-IR700 will provides an enhanced immune response and the cell comprises a T-cell as the BMS-936558 specifically blocks PD-1 wherein blockade of PD-1 expressed on T
cells can overcome immune resistance.
The BMS-936559-IR700 encompasses the anti-PD-L1-IR700 conjugate of the instant claims, has the same properties and is capable of the same functions, such as greater than 90% of the conjugate in the composition is present as a main monomer component.
It would have been predictable to one of ordinary skill in the art that the BMS-936559-IR700 will not comprise any detectable aggregates as Kobayashi et al. teaches that no detectable aggregates of the antibody-IR700 were determined by HPLC.
Kobayashi further discloses that the treated cell is contacted with the composition in an amount and under conditions sufficient for the desired response (column 12, lines 25-27).
The BMS-936559-IR700 encompasses the anti-PD-L1-IR700 conjugate of the instant claims, has the same properties and is capable of the same functions, such as the anti-PD-L1-IR700 conjugate exhibits phototoxicity upon illumination to kill an immune cell, such as a T cell, a B cell, a myeloid cell or macrophage expressing PD- L1 in the microenvironment of a tumor, thereby enhancing immune response.
Response to Arguments
Applicant asserts that the proportion of conjugate present as monomer in a composition directly reflects the stability and functional integrity of the composition. When silicon phthalocyanine dye conjugates aggregate, chromophores can become sequestered within higher molecular weight species, thereby reducing effective phototoxic activity, altering pharmacological behavior and diminishing potency for killing tumor cells. At the time of the present application was filed, IR700 was believed to be highly photostable and not in need of protection from light. The present application demonstrates, however, that aggregation can occur, including aggregation induced by light exposure, and that such aggregation negatively affects conjugate performance. Maintaining a predominantly monomeric composition is therefore not incidental, but technically significant. The anti-PD-L1-IR700 conjugate compositions exhibit greater than 96% monomer content and retain potent light-dependent cytotoxic activity. A composition in which greater than 90% of the conjugate retains monomeric preserves phototoxic function and reflects improved stability.
The instant claims do not exclude aggregates as aggregates have a main monomer component and are not drawn of a method of protecting the silicon phthalocyanine dye and PD-L1 targeting molecule conjugates via all necessary conditions.
The instant claims are drawn to a silicon phthalocyanine dyes and PD-L1 targeting molecules.
The references of Kobayashi et al., Nakajima et al., Brahmer et al., and Norde are stated above.
The BMS-936559-IR700 encompasses the anti-PD-L1-IR700 conjugate of the instant claims, has the same properties and is capable of the same functions, such as greater than 90% of the conjugate in the composition is present as a main monomer component under analogous conditions.
The disclosure does not describe a representative number of examples of the combinations of silicon phthalocyanine dyes and PD-L1 targeting molecules and/or all necessary conditions that provide a main monomer component in greater than 90% of the conjugate in the composition.
Applicant asserts that Kobayashi et al. does not teach or suggest an anti-PD-L1 targeting moiety and thus cannot teach or suggest a composition comprising anti-PD-L1-IR700 phototoxic conjugate as claimed. None of the references teach or suggest a composition comprising a conjugate with decreased aggregation in which greater than 90% is present as the main monomer component. There is no discussion of monomer percentage, aggregation control or stability to render this structural limitation obvious.
The instant claims do not exclude aggregates as aggregates have a main monomer component and are not drawn of a method of protecting the silicon phthalocyanine dye and PD-L1 targeting molecule conjugates via all necessary conditions.
The references of Kobayashi et al., Nakajima et al., Brahmer et al., and Norde are stated above.
The reference of Kobayashi et al. further teaches that no detectable aggregates of the antibody-
IR700 were determined by HPLC.
It would have been predictable to one of ordinary skill in the art that the BMS-936559-IR700 will not comprise any detectable aggregates as Kobayashi et al. teaches that no detectable aggregates of the antibody-IR700 were determined by HPLC.
The BMS-936559-IR700 encompasses the anti-PD-L1-IR700 conjugate of the instant claims, has the same properties and is capable of the same functions, such as greater than 90% of the conjugate in the composition is present as a main monomer component under analogous conditions.
Applicant asserts that the advantageous results support a finding of non-obviousness. The proportion of conjugate present in a composition as the “main monomer component” directly reflects the physical and chemical stability of the composition. Reduced monomer content and increased aggregation can be associated with diminished potency (e.g., due to the dye being sequestered into aggregates). As demonstrated in the present application, the anti-PD-L1-IR700 conjugate compositions exhibit greater than 96% monomer content. This conjugate composition provides and effective agent for
PIT-mediated tumor cell killing.
This application further demonstrates that a composition comprising anti-PD-L1-IR700 conjugate with these features can kill cancer cells. For example, Example 16C shows that, following administration of such a composition and illumination, anti-PD-L1-IR700 enhances cytotoxicity in the BxPC3 cancer cell line. As depicted in FIG. 19C, treatment with illumination resulted in significantly greater cell killing compared to treatment without illumination and illumination alone without conjugate.
The recitation of “enhanced cytotoxicity” and “significantly greater cell killing” are subjective statements.
Also, the arguments of counsel cannot take the place of evidence in the record. Examples of attorney statements are not evidence and must be supported by an appropriate affidavit or declaration
include statements regarding unexpected results. MPEP § 716.01 (c).
Conclusion
No claims are allowed at this time.
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/MELISSA J PERREIRA/Examiner, Art Unit 1618
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