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 .
Claim Status
Claims 4-5, 7, and 10 are cancelled. Claims 1-3, 6, and 8-9 as filed on 25 March 2023 are pending and under examination.
Specification
The disclosure is objected to because of the following informalities: Figure 1 has parts A and B while the Figure description does not mention or describe these separate parts.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
See page 12 in lines 18-20. Please check the entire specification to make sure no other hyperlinks are present.
Appropriate correction is required.
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 6 and 8-9 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.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or it may be satisfied by the disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
Scope of the Claimed Genus
Claim 6 is to two alternative macrophages one being an isolated macrophage conditionally expressing a specific P2Y6 inhibitor.
The claims further require a composition comprising it, further comprising an excipient in claim 8, or an immune checkpoint inhibitor in claim 9.
Summary of Species Disclosed in the original specification
Applicant discloses an isolated P2Y6 knock-out macrophage (Figures 8-9).
Applicant lists a number of P2Y6 inhibitors and states they can be put into a genetically engineers macrophage on page 25 Example 3 in paragraph 1 of this example. Applicant states these modified macrophages can be adoptive macrophage transfer as described in the literature and cites Ma et al. 2015, Brain Behaviour Immunity 45:157-170 (PTO-892); Parsa et al. 2012, Diabetes 61:2881-2892 (PTO-892); Wang et al. 2007, Kidney Int 72:290- 299 (PTO-892); and Zhang et al. 2014, Glia 62:804-817 (PTO-892).
Ma discloses adoptive transfer, which is the administration of immune cells to a patient, of macrophages and discloses different populations of macrophage: the M1 classically activated pro-inflammatory and M2 alternatively anti-inflammatory macrophages. These two populations develop based on outside stimulus and have different therapeutic properties (abstract).
Parsa teaches the adoptive transfer of macrophages in type 1 diabetic mice and the induction of the different macrophage populations and the effectiveness of macrophages in preventing diabetes in mice (abstract and Figure 1).
Wang teaches the adoptive transfer of M1 and M2 macrophage for the study of kidney disease in a mouse model as macrophage infiltration is a prominent feature associated with the severity of renal injury and progressive renal failure (Abstract).
Zhang teaches the culture conditions of isolated macrophages alter the phenotype of the macrophage and that cultured macrophage with a robust M2 phenotype can be used therapeutically using adoptive transfer (abstract).
None of these cited art provide examples of modified macrophages producing a small molecule or a P2Y6 inhibitor.
Applicant discloses one specific pharmacological inhibitor MRS2578 (Example 2 and Figure 5 and 7). Applicant does not disclose a modified macrophage producing or expressing MRS2578 or any inhibitor of P2Y6. The art cited by applicant does not provide examples of an isolated macrophage that conditionally expresses a P2Y6 inhibitor.
Applicant does not disclose any working examples of a modified macrophage expressing a P2Y6 inhibitor.
State of the Relevant Art
The only P2Y6 applicant has shown in a pharmaceutical composition is MRS2578. MRS2578 is a small molecule (Mamedova et al. 2004, Biochem Pharmacol 67:1763-1770 (PTO-892) in abstract, Table 1 and Figures 1-2). The art does not provide any guidance on how a macrophage with a vector would express MRS2578.
The art cited by applicant in the disclosure and previously discussed only teach the different macrophage subtypes, their use as therapeutics, methods of culturing isolated macrophage and inducing phenotypes of interest, and adoptive transfer of macrophage for use as a therapeutic (Ma et al. 2015, Brain Behaviour Immunity 45:157-170 (PTO-892); Parsa et al. 2012, Diabetes 61:2881-2892 (PTO-892); Wang et al. 2007, Kidney Int 72:290- 299 (PTO-892); and Zhang et al. 2014, Glia 62:804-817 (PTO-892)).
The art teaches genetically modified macrophages (GEMs) that can be transformed using lentiviral vectors (Moyes et. al. Human Gene Therapy. 28(2):200-215. (2017) (PTO-892) (abstract and page 202 in col 2 in par 1). Moyes teaches macrophages can stably express lentivirally encoded genes but notes the need to optimize to provide for stability of macrophages and safety for patients (page 204 in col 2 in par 2 to page 205 in col 2 in par 1).
The art and applicant teach that macrophages express P2Y6 (page 2 of instant application in lines 33-34, Figures 1-2, and Bar et. al. Molecular Pharmacology. 74(3):(777-784) (2008) (IDS 03/24/2023 NPL 1).
Neither the applicant nor the art teaches how a macrophage would be modified to express P2Y6 inhibitors broadly or MRS2578 specifically.
Neither applicant nor the art has shown if an isolated macrophage expressing a P2Y6 inhibitor would survive or if the inhibitor would have activity.
Are the disclosed species representative of the claimed genus?
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The specification discloses no versions of the invention. The only disclosures are declarative statements none of which have been reduced to practice.
A complete lack of discloses species means they are not representative.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed binding activity.
The applicant has listed a number of known in the art types of inhibitors and provides one working P2Y6 inhibitor in MRS2578. The stated limitations of the claim are to an isolated macrophage expressing the inhibitor which could not be done with MRS2578. The many types of inhibitors in the chemical and biological world vary based on building blocks as some are chemical, RNA, DNA, or proteins. The inhibitors vary in how they are made, whether they would be toxic in a macrophage, or how they would act as inhibitors. They do not share a common structure.
Conclusion:
For all of the reasons presented above, one of skill in the art would not know what applicant had possession of at the time of the application was filed as the specification merely provides types of inhibitors and theorizes the use of one specific P2Y6 inhibitor in the modified macrophage of the claims. Therefore, the skilled artisan would not reasonably conclude that the inventors possession of the modified macrophages as broadly claimed at the time the application was filed. Given the lack of shared structural properties that provide the claimed binding activity, the lack of described species which cannot be representative of a genus applicant was not in possession of the invention as claimed.
Claims 6 and 8-9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a composition comprising an isolated P2Y6 knock-out macrophage, does not reasonably provide enablement for a composition comprising an isolated macrophage conditionally expressing a specific P2Y6 inhibitor. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described in In re Colianni, 195 USPQ 150 (CCPA 1977) and have been adopted by the Board of Patent Appeals and Interferences in Ex Parte Forman, 230 USPQ 546 (BPAI 1986). Among these factors are:
1. the nature of the invention,
2. the state of the prior art,
3. the predictability or lack thereof in the art,
4. the breadth of the claims,
5. the amount of direction or guidance present, and
6. the presence or absence of working examples.
The following is an analysis of these factors in relationship to this application.
Breadth of Claims
Claim 6 is to two alternative macrophages one being an isolated macrophage conditionally expressing a specific P2Y6 inhibitor.
The claims further require a composition comprising it, further comprising an excipient in claim 8, or an immune checkpoint inhibitor in claim 9.
Guidance/Working Examples
Applicant discloses an isolated P2Y6 knock-out macrophage (Figures 8-9).
Applicant lists a number of P2Y6 inhibitors and states they can be put into a genetically engineers macrophage on page 25 Example 3 in paragraph 1 of this example. Applicant states these modified macrophages can be adoptive macrophage transfer as described in the literature and cites Ma et al. 2015, Brain Behaviour Immunity 45:157-170 (PTO-892); Parsa et al. 2012, Diabetes 61:2881-2892 (PTO-892); Wang et al. 2007, Kidney Int 72:290- 299 (PTO-892); and Zhang et al. 2014, Glia 62:804-817 (PTO-892).
Ma discloses adoptive transfer, which is the administration of immune cells to a patient, of macrophages and discloses different populations of macrophage: the M1 classically activated pro-inflammatory and M2 alternatively anti-inflammatory macrophages. These two populations develop based on outside stimulus and have different therapeutic properties (abstract).
Parsa teaches the adoptive transfer of macrophages in type 1 diabetic mice and the induction of the different macrophage populations and the effectiveness of macrophages in preventing diabetes in mice (abstract and Figure 1).
Wang teaches the adoptive transfer of M1 and M2 macrophage for the study of kidney disease in a mouse model as macrophage infiltration is a prominent feature associated with the severity of renal injury and progressive renal failure (Abstract).
Zhang teaches the culture conditions of isolated macrophages alter the phenotype of the macrophage and that cultured macrophage with a robust M2 phenotype can be used therapeutically using adoptive transfer (abstract).
None of these cited art provide examples of modified macrophages producing a small molecule or a P2Y6 inhibitor.
Applicant discloses one specific pharmacological inhibitor MRS2578 (Example 2 and Figure 5 and 7). Applicant does not disclose a modified macrophage producing or expressing MRS2578 or any inhibitor of P2Y6. The art cited by applicant does not provide examples of an isolated macrophage that conditionally expresses a P2Y6 inhibitor.
Applicant does not disclose any working examples of a modified macrophage expressing a P2Y6 inhibitor. Applicant does not disclose how to make or use a macrophage that conditionally expresses a P2Y6 inhibitor.
State of the Art/Predictability
The only P2Y6 applicant has shown in a pharmaceutical composition is MRS2578. MRS2578 is a small molecule (Mamedova et al. 2004, Biochem Pharmacol 67:1763-1770 (PTO-892) in abstract, Table 1 and Figures 1-2). The art does not provide any guidance on how a macrophage with a vector would express MRS2578.
The art cited by applicant in the disclosure and previously discussed only teach the different macrophage subtypes, their use as therapeutics, methods of culturing isolated macrophage and inducing phenotypes of interest, and adoptive transfer of macrophage for use as a therapeutic (Ma et al. 2015, Brain Behaviour Immunity 45:157-170 (PTO-892); Parsa et al. 2012, Diabetes 61:2881-2892 (PTO-892); Wang et al. 2007, Kidney Int 72:290- 299 (PTO-892); and Zhang et al. 2014, Glia 62:804-817 (PTO-892)).
The art teaches genetically modified macrophages (GEMs) that can be transformed using lentiviral vectors (Moyes et. al. Human Gene Therapy. 28(2):200-215. (2017) (PTO-892) (abstract and page 202 in col 2 in par 1). Moyes teaches macrophages can stably express lentivirally encoded genes but notes the need to optimize to provide for stability of macrophages and safety for patients (page 204 in col 2 in par 2 to page 205 in col 2 in par 1).
The art and applicant teach that macrophages express P2Y6 (page 2 of instant application in lines 33-34, Figures 1-2, and Bar et. al. Molecular Pharmacology. 74(3):(777-784) (2008) (IDS 03/24/2023 NPL 1).
Conclusion
Neither the applicant nor the art teaches how a macrophage would be modified to express P2Y6 inhibitors broadly or MRS2578 specifically. One of skill in the art would not know how an isolated modified macrophage could conditionally express P2Y6 inhibitors. One of skill in the art would not know whether the modification of a macrophage to express a P2Y6 inhibitor would be viable isolated or if the inhibitor would function on the macrophage expressing itself or be produced and excreted by the cell. One of skill in the art would then not know how to make or use an isolated macrophage conditionally expressing a P2Y6 inhibitor.
The applicant and the art provides a method of making and using an isolated P2Y6 knock-out macrophage.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 6 and 8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bar et. al. Molecular Pharmacology. 74(3):(777-784) (2008) (IDS 03/24/2023 NPL 1).
Regarding claims 6 and 8, Bar teaches mutant mice with inactivated or knockout P2Y6 macrophages that were isolated (page 778 in col 1 in last paragraph and col 2 in last paragraph and Figure 1). Bar confirms they are knockout macrophages that are further cultured. Cultured macrophages would have macrophages in culture conditions which would comprise excipients (page 780 in col 2 in final paragraph and Figure 2).
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over Carleton (WO 2019/1401150 A1) (IDS), Thevananther (WO 2017/070660 A1) (IDS), Golz (WO 2004/106937 A2) (IDS), and Yebdri et. al. Eur. J. Immunol. 39:2885-2894. (2009) (IDS),
Carleton teaches the combination of anti-PD-1 and anti-IL-8 antibodies for use in cancer therapy (abstract). The antibodies of the invention are inhibitory of PD-1 and PD-L1 and IL-8 (page 14 in par 1 and page 16 in par 1 in particular the last line).
Carleton teaches the combination inhibitory therapy targeting PD-1 and IL-8 pathways.
Carleton does not teach a P2Y6 inhibitor for use in this combination.
These deficiencies are filled by Thevananther, Golz, Yebdri.
Regarding claims 1-2, Thevananther teaches the use of P2Y6 inhibitors in the treatment of cancer (abstract). Thevananther teaches a number of inhibitors including MRS2578 ([0004]). Thevananther teaches the use of MRS2578 in a method of inhibiting cancer cells (claims 1-2).
Golz teaches the expression of P2Y6 in various tissues of interest including the brain (page 5 in lines 1-5) and cancers including stomach, liver, lung, cervix tumor, uterus, ovary, and kidney (page 62 in lines 25-31 and page 63 in lines 1-5). Golz teaches the modulation of P2Y6 (page 63 in lines 4-5).
Yebdri teaches the administration of MRS2578, a P2Y6 inhibitor, decreased IL-8 secretion (abstract).
It would have been obvious at the time the application was filed to substitute the IL-8 inhibitor of the combination therapy comprising PD-1 inhibition and IL-8 inhibition for use in a method of treating cancer of Cartleton with the P2Y6 inhibitor MRS2578 taught by Thevananther and Yebdri. It would have been obvious to substitute the IL-8 inhibiting antibodies of Carleton with MRS2578 as Yebdri teaches MRS2578 when used as a P2Y6 inhibitor decreased IL-8 secretion. PD-1 antibodies and MRS2578 are both taught for use in the treatment of cancer making their combination prima facie obvious. Further, Carleton teaches the combination of targeting PD-1 and IL-8 signaling by inhibition which in combination of Yebdri teaches towards the combination of inhibition of PD-1 and MRS2578 inhibition of P2Y6. There would have been a reasonable expectation of success as both PD-1 immune checkpoint inhibitors and P2Y6 inhibitor MRS2578 are known in the art for the treatment of cancer.
Claims 6 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Bar et. al. Molecular Pharmacology. 74(3):(777-784) (2008) (IDS 03/24/2023 NPL1) and Hartley et al. Cancer Immunol Res. 6(10:1260-1273. (2018) (PTO-892).
Bar teaches mice with knockout P2Y6 macrophage and the isolation and culture of those knockout macrophage (abstract and page 778 in col 2 in las paragraph and page 779 in lines 1-9). Bar further teaches the characterization of the isolated macrophages to determine their activity in response to stimulus (Figures 3-4). By teaching isolated knockout macrophages in culture conditions Bar is teaching P2Y6 knockout macrophage in a composition comprising an excipient.
Bar does not teach the composition further comprising an immune checkpoint inhibitor.
This deficiency is filled by Hartley.
Hartley teaches that PD-L1 is expressed on macrophages including tumor associated macrophages (TAM) and plays a role in macrophage activity which is of interest in the tumor micro environment (TME) (abstract and page 1261 in col 1 in par 1). Hartley teaches the isolation of monocytes and culturing of macrophages including knockout macrophages from mice (page 1261 in col 1 in last paragraph and col 2 in lines 1-14). Hartley teaches culturing isolated macrophages with PD-L1 antibodies resulted in changes to macrophage proliferation, size, and activation (Figures 1-2). Hartley teaches its antibodies are acting as inhibitors (page 1263 in col 2 in par 4). Hartley teaches in vivo experiments that showed treatment with PD-1/PD-L1 antibodies resulted in increased tumor infiltration with activated macrophages and reduced tumor growth (abstract).
It would have been obvious at the time the application was filed to substitute the macrophage culture treatments of the P2Y6 knockout macrophage of Bar with culture treatment with anti-PD-L1 antibodies as taught by Hartley. One of skill in the art would have been motivated to further characterize the macrophages of Bar by treatment with PD-L1 antibodies as they are shown to change macrophage activity in in vitro and in vivo and the role of macrophage in anti-tumor activity. One of skill in the art would have wanted to further characterize the knockout of Bar and the TME as macrophage are of interest as targets for cancer therapeutics. There would have been a reasonable expectation of success as Bar and Hartley are teaching the isolation and culturing of murine macrophage and testing their response to stimulus to characterize the pathways of the macrophage.
Conclusion
No claims allowable.
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/F.E./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643