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 2-13, 15-25, 27-28, 31-38, 41-50, 57-122, and 127-128 have been cancelled and claims 1, 14, 26, 29-30, 39-40, and 51-53 have been amended, as requested in the amendment filed on 09/18/2025. Following the amendment, claims 1, 14, 26, 29-30, 39-40, 51-56, and 123-126 are pending in the instant application.
Claims 1, 14, 26, 29-30, 39-40, 51-56, and 123-126 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1, 14, 26, 29-30, 39-40, 51-56, and 123-126 have an effective filing date of April 17, 2019 corresponding to PRO 62/835,488.
Specification - Objections Withdrawn
With regard to the objections to the specification, it is noted that Applicant has: (i) amended the abstract such that it is now between 50 and 150 words; (ii) amended the specification to remove any embedded hyperlinks or other forms of browser executable code; and (iii) indicated that the trademarks utilized in the specification are assay kits which do not have generic terminology, but disclosures regarding said assays are referred to as “non-radioactive assay methods” and the specific kits are provided by their trademark name for purchase as examples. In view of the above, the objections to the specification are withdrawn.
Claim Rejections - 35 USC § 112 - Withdrawn
Claims 51-52 were 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.
Applicant has amended claims 51 and 52 such that they now recite “comprises the sequence set forth in SEQ ID NO:36”. The claims are now considered to be clear and definite, and as such the rejection of claims 51-52 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn.
Claim Rejections - 35 USC § 102 - Withdrawn
Claims 1, 13-15, 18, 26, 29-30, 39-41, 51-56, and 123-128 were rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO 2019/079520 A2 (previously cited on PTO-892; herein after referred to as "Evans").
Applicant’s arguments, see page 11 of Remarks, filed 09/18/2025, with respect to Evans not qualifying as prior art under 35 U.S.C. 102(a)(2) by way of the exception under 102(b)(2)(C) have been fully considered and are deemed persuasive. See page 9 of Remarks for statement of common ownership. The rejection of claims 1, 13-15, 18, 26, 29-30, 39-41, 51-56, and 123-128 under 35 U.S.C. 102(a)(2) as being anticipated by Evans is withdrawn.
Claim 7 was rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by WO 2019/079520 A2 (previously cited on PTO-892; herein after referred to as "Evans").
Applicant has cancelled claim 7, rendering the rejection moot. As such, the rejection of claim 7 under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Evans is withdrawn.
Claims 1, 7, 13-15, 18, 26, 29-30, 39-41, 51-56, and 123-126 were rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by WO 2017/181148 A2 (previously cited on PTO-892; herein after referred to as “Swanson”).
Applicant has amended claim 1 such that it now recites “reducing Grade II-IV acute graft versus host disease (aGVHD), wherein the aGVHD is resistant or refractory to treatment with an immunosuppressant, and wherein the immunosuppressant comprises a corticosteroid or a cyclosporine”. On pages 11-12 of Remarks, Applicant argues that the amendment above renders the rejection with regard to claim 1 moot, and subsequently claims 14, 26, 29, 39-40, 51-56, and 123-126 as they all depend from claim 1. It is noted that Swanson alone does not teach claim 1 as amended, and as such the rejection of claims 1, 7, 13-15, 18, 26, 29-30, 39-41, 51-56, and 123-126 under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Swanson is withdrawn.
Claim Rejections - 35 USC § 103 - Withdrawn
Claims 127-128 were rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/181148 A2 (previously cited on PTO-892; herein after referred to as “Swanson”).
Applicant has cancelled claims 127-128, rendering the rejection moot. As such, the rejection of claims 127-128 127-128 under 35 U.S.C. 103 as being unpatentable over Swanson is withdrawn.
Claim Rejections - 35 USC § 103 - New
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 14, 26, 29-30, 39-40, 51-56, and 123-126 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/181148 A2 (previously cited on PTO-892; herein after referred to as “Swanson”) in view of non-patent literature by Li et. al. (Expert Opin. Pharmacother., 2008, 9(13), 2305-2316; herein after referred to as "Li").
With regard to claim 1, Swanson teaches immunomodulatory proteins comprising ICOSL variants and nucleic acids encoding such proteins wherein the immunomodulatory proteins provide therapeutic utility for a variety of immunological and oncological conditions and compositions and methods for making and using such proteins are provided (Abstract). In some embodiments, the immune response is decreased by the provided methods of modulating the immune response: a variant ICOSL polypeptide or immunomodulatory protein that is soluble is administered to the subject wherein the soluble polypeptide or immunomodulatory protein can be an Fc fusion protein; or a pharmaceutical composition, which can comprise a variant ICOSL polypeptide according to any one of the provided embodiments or the immunomodulatory protein according to any one of the provided embodiments, is administered to the subject (Paragraph 0056). The terms "treating," "treatment," or "therapy" of a disease or disorder as used herein mean slowing, stopping or reversing the disease or disorders progression, as evidenced by
decreasing, cessation or elimination of either clinical or diagnostic symptoms, by administration
of a therapeutic composition (e.g., containing an immunomodulatory protein or engineered cells)
of the invention either alone or in combination with another compound; "treating," "treatment," or "therapy" also means a decrease in the severity of symptoms in an acute or chronic disease or disorder or a decrease in the relapse rate as for example in the case of a relapsing or remitting autoimmune disease course or a decrease in inflammation in the case of an inflammatory aspect of an autoimmune disease (Paragraph 0150). Swanson teaches that the variant ICOSL polypeptide has one or more amino acid modification, e.g., substitution in an unmodified ICOSL or specific binding fragment thereof corresponding to position(s) 52, 84, 91, 119, 155, 168, 207 with reference to numbering of SEQ ID NO:32 such that the variant ICOSL polypeptide has one or more amino acid modification, e.g., substitution selected from A91S, N52H, N52Q, N84Q, Nl19Q, N155H, N155Q, N168Q, N207Q; in some embodiments, the variant ICOSL polypeptide comprises any of the extracellular domain (ECD) sequences set forth in SEQ ID NOs: 387-424, 427-433, 435-470 (Paragraphs 0204-0205). It is specifically noted that, for example, Swanson SEQ ID NOs: 436, 448, and 470 all comprise N52H/N57Y/Q100R substitutions. In some embodiments of any one of the variant ICOSL polypeptides, the variant ICOSL polypeptide is linked to a multimerization domain wherein some embodiments, the multimerization domain is an Fc domain or a variant thereof with reduced effector function (Paragraph 0029). In some embodiments, an administered dose of the pharmaceutical composition is about 1 μg of protein per kg subject body mass or more (such as about 2 μg of protein per kg subject body mass or more, about 5 μg of protein per kg subject body mass or more, about 10 μg of protein per kg subject body mass or more, about 25 μg of protein per kg subject body mass or more, about 50 μg of protein per kg subject body mass or more, about 100 μg of protein per kg subject body mass or more, about 250 μg of protein per kg subject body mass or more, about 500 μg of protein per kg subject body mass or more, about 1 mg of protein per kg subject body mass or more, about 2 mg of protein per kg subject body mass or more, or about 5 mg of protein per kg subject body mass or more) (Paragraph 0399). In some embodiments, the pharmaceutical composition is administered to modulate an autoimmune condition; the pharmaceutical compositions described are used to limit or prevent graft-related or transplant related diseases or disorders, such as graft versus host disease (GVHD) and/or to suppress autoimmune rejection of transplanted or grafted bone marrow, organs, skin, muscle, neurons, islets, or parenchymal cells (Paragraph 0413). It is noted Swanson does not explicitly teach treating acute GHVD, but the definition of “treating” includes both acute and chronic conditions. Thus, by definition, acute GHVD is a condition that can be treated with the variant ICOSL polypeptides/compositions of the invention. Thus, Swanson teaches a method for treating (i.e., reducing) GVHD (which can include acute GVHD) comprising administering one or more doses of a variant ICOSL polypeptide linked to a multimerization domain (e.g., an immunoglobulin Fc domain) wherein the variant ICOSL polypeptide is an ICOSL extracellular domain or portion thereof comprising an IgV domain or specific binding fragment thereof that comprises one or more amino acid substitutions selected from N52H, N27Y, and Q100R with reference to instant SEQ ID NO: 1 (e.g., reference SEQ ID NOs: 436, 448, and 470) wherein each of the one or more doses of the variant ICOSL fusion protein is administered in an amount from at or about 0.1 mg/kg to at or about 20 mg/kg (see Paragraph 0399). However, Swanson does not teach or suggest aGVHD that is Grade II-IV, nor aGVHD that is resistant or refractory to an immunosuppressant comprising a corticosteroid or cyclosporine. This deficiency is remedied by Li.
Li teaches that allogeneic hematopoietic stem cell transplantation offers great promise for the treatment of a variety of diseases including malignancies and other diseases of hematopoietic origin; however, morbidity and mortality due to graft-versus-host disease (GVHD) remain a major barrier to its application (Abstract). In GVHD), donor immune cells attack the immunocompromised recipient cells resulting in multi-organ damage; GVHD may occur in acute or chronic form wherein acute GVHD usually manifests in 20 – 40 days, or as late as 2 months, after allogeneic HSCT while chronic GVHD has a later onset, usually after 100 days following transplantation, and may develop as an extension of acute GVHD, or de novo (Page 2305, Introduction). Acute GVHD mainly affects the skin, gastrointestinal tract, lung and liver, and the
stage of GVHD is determined by a system that quantifies the extent of skin involvement (rash), diarrhea, and serum bilirubin level, ranging from grade I for minimal to grade IV for severe disease (Pages 2305-2306). Despite prophylaxis, acute GVHD (grade II – IV) occurs in 30 – 60% of patients after allogeneic HSCT from HLA-identical sibling donors and its incidence increases when grafts come from HLA-matched unrelated or HLA-mismatched donors, and when recipients are older or positive for cytomegalovirus (CMV); the mortality from acute
GVHD can reach as high as 50% (Page 2306, First Full Paragraph). Li also discloses that corticosteroids are the current standard of care for first-line therapy of acute GVHD, wherein primary treatment of acute GVHD is prednisone or methylprednisone (2 mg/kg/day, IV)
for 5 or 7 days; a 5-day course of corticosteroids is sufficient to identify steroid-refractory
acute GVHD, wherein non-responders should receive second-line therapy (Page 2310, First-Line Treatment). Patients who do not respond to first-line steroid therapy are generally treated with higher-dose steroids, wherein if a response is observed in 3 – 5 days, the dose is decreased to
2 mg/kg/day and the patients are treated in a way similar to individuals who respond to low-dose steroid therapy; however, < 60% of steroid-refractory patients responded well to second-line treatment (Page 2310, Second-Line Treatment). Li further discloses that inducible co-stimulator (ICOS) is expressed on activated CD4+ and CD8+ T cells, and the ligand for ICOS (ICOS-L) is constitutively expressed on B cells, macrophages, and dendritic cells and is upregulated on some non-lymphoid tissues by TNF-α or LPS; the blockade of ICOS/ICOS-L interaction by using ICOS -/- mice or anti-ICOS mAbs has been shown to reduce CD4+ and CD8+ T cell-mediated GVHD under lethal irradiation conditions (Page 2307, Column 2, Last Paragraph). Li specifically indicates that ICOS/ICOS-L blockade might be an especially attractive target for downregulating T-cell responses in GVHD once it has been initiated (Id.).
Swanson and Li are considered to be analogous to the present invention as they are in the same field of transplant related diseases or disorders, such as GVHD (including aGVHD) and therapeutics therefor. Thus, it would have been obvious to one of ordinary skill in the art that the method of treating (i.e., reducing) GVHD (which can include acute GVHD) taught by Swanson could be modified such that the method is specifically applied in cases of aGVHD, including Grades II-IV, wherein said aGVHD is refractory to corticosteroids because combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to modify the method of Swanson such that it is applied in cases aGVHD, including Grades II-IV, wherein said aGVHD is refractory to corticosteroids in order to more effectively treat aGVHD that cannot be controlled by typical first- and second-line therapies in order to improve patient outcomes, because Li specifically indicates that ICOS/ICOS-L blockade might be an especially attractive target for downregulating T-cell responses in GVHD once it has been initiated (emphasis added).
With regard to claim 14, Swanson teaches that, in some embodiments, an administered dose of the pharmaceutical composition is about 1 μg of protein per kg subject body mass or more (such as about 2 μg of protein per kg subject body mass or more, about 5 μg of protein per kg subject body mass or more, about 10 μg of protein per kg subject body mass or more, about 25 μg of protein per kg subject body mass or more, about 50 μg of protein per kg subject body mass or more, about 100 μg of protein per kg subject body mass or more, about 250 μg of protein per kg subject body mass or more, about 500 μg of protein per kg subject body mass or more, about 1 mg of protein per kg subject body mass or more, about 2 mg of protein per kg subject body mass or more, or about 5 mg of protein per kg subject body mass or more) (Paragraph 0399). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 26, Swanson teaches the dosage of pharmaceutical compositions of the invention are a single dose or a repeated dose: the doses are given to a subject once per day, twice per day, three times per day, four or more times per day; about 1 or more (such as about 2 or more, about 3 or more, about 4 or more, about 5 or more, about 6 or more, or about 7 or more) doses are given in a week; or multiple doses are given over the course of days, weeks, months, or years wherein a course of treatment is about 1 or more doses (such as about 2 or more does, about 3 or more doses, about 4 or more doses, about 5 or more doses, about 7 or more doses, about 10 or more doses, about 15 or more doses, about 25 or more doses, about 40 or more doses, about 50 or more doses, or about 100 or more doses) (Paragraph 0398). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 29-30, Swanson teaches that, in some embodiments, an administered dose of the pharmaceutical composition is about 1 μg of protein per kg subject body mass or more (such as about 2 μg of protein per kg subject body mass or more, about 5 μg of protein per kg subject body mass or more, about 10 μg of protein per kg subject body mass or more, about 25 μg of protein per kg subject body mass or more, about 50 μg of protein per kg subject body mass or more, about 100 μg of protein per kg subject body mass or more, about 250 μg of protein per kg subject body mass or more, about 500 μg of protein per kg subject body mass or more, about 1 mg of protein per kg subject body mass or more, about 2 mg of protein per kg subject body mass or more, or about 5 mg of protein per kg subject body mass or more) (Paragraph 0399). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 39-40, Swanson teaches that the pharmaceutical compositions of the invention are administered to a subject through any route, including orally, transdermally, by inhalation, intravenously, intra-arterially, intramuscularly, direct application to a wound site, application to a surgical site, intraperitoneally, by suppository, subcutaneously, intradermally, transcutaneously, by nebulization, intrapleurally, intraventricularly, intra-articularly, intraocularly, or intraspinally (Paragraph 0397). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 51-52, Swanson teaches SEQ ID NOs: 436, 448, and 470, all of which comprise 100% matches to instant SEQ ID NO: 36 and comprise the recited amino acid substitutions. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 53-56 and 123, Swanson teaches that in some embodiments of any one of the variant ICOSL polypeptides, the variant ICOSL polypeptide is linked to a multimerization domain wherein some embodiments, the multimerization domain is an Fc domain or a variant thereof with reduced effector function (Paragraph 0029). The Fc can be murine or human Fc wherein the Fc is a mammalian or human IgGl, lgG2, lgG3, or lgG4 Fc region (Paragraph 0215). One or more amino acid modifications may be introduced into
the Fc region of an ICOSL-Fc variant fusion, thereby generating an Fc region variant wherein, in some embodiments, the Fc region variant has decreased effector function (Paragraph 0217). ICOSL-Fc variant fusions with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 by EU numbering; such alterations of the Fc region include, for example, IgGl-N297G and IgGl-L234A/L235E/G237A (Paragraphs 0219-0220). Additionally, Swanson discloses an ICOSL-Fc variant fusion comprising a variant Fc region in which the variant Fc comprises the sequence of amino acids set forth in any of SEQ ID NOS: 474, 476, 477, 478 or 507, wherein Swanson SEQ ID NOs: 477 and 474 are 100% matches to instant SEQ ID NOs: 40 and 41, respectively. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 124-126, Swanson teaches that the variant ICOSL polypeptide can be indirectly linked to the Fc sequence, such as via a linker; in some embodiments, the linker is (in one-letter amino acid code): GGGGS ("4GS") or multimers of the 4GS linker, such as repeats of 2 (i.e., GGGGSGGGS), 3 (i.e., GGGSGGGSGGGS), 4, or 5 4GS linkers. Thus, Swanson teaches linkers, including those of instant SEQ ID NOs: 52-54. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
Double Patenting - Updated
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
The double-patenting rejections of record are newly updated below to account for the amendment of instant claim 1.
Claims 1, 14, 26, 29-30, 39-40, 51-56, and 123-126 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 19-22, 25-26, and 29-30 of copending Application No. 18/172,258 (herein after referred to as “’258”) in view of WO 2017/181148 A2 (previously cited on PTO-892; herein after referred to as “Swanson”) and Li et. al. (Expert Opin. Pharmacother., 2008, 9(13), 2305-2316; herein after referred to as "Li").
Claims 1, 14, 26, 29-30, 39-40, 51-56, and 123-126 are rendered obvious by the combined teachings of the prior art as discussed in the 103 section, the 103 being incorporated here. The addition of the claims of copending application ‘258 over related subject matter only further supports this obviousness.
Claims 1-2 of ‘258 disclose a variant ICOSL-Fc fusion protein comprising an ICOSL polypeptide linked via a linker to an Fc region, wherein the ICOSL polypeptide is set forth in SEQ ID NO: 565, the linker is set forth in SEQ ID NO: 229, and the Fc region is set forth in SEQ ID NO: 637 (claim 1) wherein the ICOSL-Fc fusion protein is a homodimer (i.e., Fc region is a multimerization domain) (claim 2). It is noted ‘258 SEQ ID NOs: 565, 229, and 637 are 100% matches to instant SEQ ID NOs: 36, 53, and 42, respectively. Claims 19-20 of ‘258 recite pharmaceutical compositions comprising the ICOSL-Fc fusion proteins of claims 1 or 2 and claims 21-22 of ‘258 recite articles of manufacture comprising the pharmaceutical compositions of claims 19-20. Claims 25-26 of ‘258 disclose methods of modulating immune responses in a subject comprising administering the pharmaceutical compositions of claims 19 and 20, respectively. Claims 29-30 of ‘258 recite methods of treating a disease or a subject comprising administering the pharmaceutical compositions of claims 19 and 20, respectively. It is noted that the instant application comprises species of the variant ICOSL-Fc fusion proteins and methods of treatment comprising their administration as disclosed in ‘258. However, the claims of ‘258 do not disclose (i) preventing or reducing Grade II-IV aGVHD that is resistant or refractory to immunosuppressants including corticosteroids or cyclosporine nor (ii) doses of the ICOSL-Fc fusion protein. These deficiencies are addressed by the cited references, as provided by the teachings specified in the 103 section.
‘258, Swanson, and Li are considered to be analogous to the present invention as they are in the same field of modulation of immune responses (e.g., using ICOSL-based approaches). Thus, it would have been obvious to one of ordinary skill in the art to modify the generic methods of treatment disclosed by ‘258 to more specifically arrive at a method for treating (i.e., reducing) GVHD (which can include aGVHD) comprising administering a variant ICOSL fusion protein in an amount from at or about 0.1 mg/kg to at or about 20 mg/kg, as suggested by Swanson, in cases of aGVHD, including (i) Grades II-IV and (ii) wherein said aGVHD is refractory to corticosteroids, as suggested by Li, because combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to modify the method of ‘258 based on the teachings of Swanson and Li to arrive at a method of treating aGVHD, including Grades II-IV, wherein said aGVHD is refractory to corticosteroids in order to more effectively treat aGVHD that cannot be controlled by typical first- and second-line therapies in order to improve patient outcomes, because Li specifically indicates that ICOS/ICOS-L blockade might be an especially attractive target for downregulating T-cell responses in GVHD once it has been initiated (emphasis added).
With regard to claim 14, Swanson teaches that, in some embodiments, an administered dose of the pharmaceutical composition is about 1 μg of protein per kg subject body mass or more (such as about 2 μg of protein per kg subject body mass or more, about 5 μg of protein per kg subject body mass or more, about 10 μg of protein per kg subject body mass or more, about 25 μg of protein per kg subject body mass or more, about 50 μg of protein per kg subject body mass or more, about 100 μg of protein per kg subject body mass or more, about 250 μg of protein per kg subject body mass or more, about 500 μg of protein per kg subject body mass or more, about 1 mg of protein per kg subject body mass or more, about 2 mg of protein per kg subject body mass or more, or about 5 mg of protein per kg subject body mass or more) (Paragraph 0399). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claim 26, Swanson teaches the dosage of pharmaceutical compositions of the invention are a single dose or a repeated dose: the doses are given to a subject once per day, twice per day, three times per day, four or more times per day; about 1 or more (such as about 2 or more, about 3 or more, about 4 or more, about 5 or more, about 6 or more, or about 7 or more) doses are given in a week; or multiple doses are given over the course of days, weeks, months, or years wherein a course of treatment is about 1 or more doses (such as about 2 or more does, about 3 or more doses, about 4 or more doses, about 5 or more doses, about 7 or more doses, about 10 or more doses, about 15 or more doses, about 25 or more doses, about 40 or more doses, about 50 or more doses, or about 100 or more doses) (Paragraph 0398). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 29-30, Swanson teaches that, in some embodiments, an administered dose of the pharmaceutical composition is about 1 μg of protein per kg subject body mass or more (such as about 2 μg of protein per kg subject body mass or more, about 5 μg of protein per kg subject body mass or more, about 10 μg of protein per kg subject body mass or more, about 25 μg of protein per kg subject body mass or more, about 50 μg of protein per kg subject body mass or more, about 100 μg of protein per kg subject body mass or more, about 250 μg of protein per kg subject body mass or more, about 500 μg of protein per kg subject body mass or more, about 1 mg of protein per kg subject body mass or more, about 2 mg of protein per kg subject body mass or more, or about 5 mg of protein per kg subject body mass or more) (Paragraph 0399). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 39-40, Swanson teaches that the pharmaceutical compositions of the invention are administered to a subject through any route, including orally, transdermally, by inhalation, intravenously, intra-arterially, intramuscularly, direct application to a wound site, application to a surgical site, intraperitoneally, by suppository, subcutaneously, intradermally, transcutaneously, by nebulization, intrapleurally, intraventricularly, intra-articularly, intraocularly, or intraspinally (Paragraph 0397). Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 51-52, it is noted that ‘258 SEQ ID NO: 565 is a 100% match to instant SEQ ID NO: 36. Additionally, Swanson teaches SEQ ID NOs: 436, 448, and 470, all of which comprise 100% matches to instant SEQ ID NO: 36 and comprise the recited amino acid substitutions. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 53-56 and 123, ‘258 SEQ ID NO: 637 is a 100% match to instant SEQ ID NO: 42. Additionally, Swanson teaches that in some embodiments of any one of the variant ICOSL polypeptides, the variant ICOSL polypeptide is linked to a multimerization domain wherein some embodiments, the multimerization domain is an Fc domain or a variant thereof with reduced effector function (Paragraph 0029). The Fc can be murine or human Fc wherein the Fc is a mammalian or human IgGl, lgG2, lgG3, or lgG4 Fc region (Paragraph 0215). One or more amino acid modifications may be introduced into the Fc region of an ICOSL-Fc variant fusion, thereby generating an Fc region variant wherein, in some embodiments, the Fc region variant has decreased effector function (Paragraph 0217). ICOSL-Fc variant fusions with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 by EU numbering; such alterations of the Fc region include, for example, IgGl-N297G and IgGl-L234A/L235E/G237A (Paragraphs 0219-0220). Swanson also discloses an ICOSL-Fc variant fusion comprising a variant Fc region in which the variant Fc comprises the sequence of amino acids set forth in any of SEQ ID NOS: 474, 476, 477, 478 or 507, wherein Swanson SEQ ID NOs: 477 and 474 are 100% matches to instant SEQ ID NOs: 40 and 41, respectively. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
With regard to claims 124-126, ‘258 SEQ ID NO: 229 is a 100% match to instant SEQ ID NO: 53. Additionally, Swanson teaches that the variant ICOSL polypeptide can be indirectly linked to the Fc sequence, such as via a linker; in some embodiments, the linker is (in one-letter amino acid code): GGGGS ("4GS") or multimers of the 4GS linker, such as repeats of 2 (i.e., GGGGSGGGS), 3 (i.e., GGGSGGGSGGGS), 4, or 5 4GS linkers. Thus, Swanson teaches linkers, including those of instant SEQ ID NOs: 52-54. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective filing date of the invention as evidenced by the references.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 7, 13-15, 18, 26, 29-30, 39-41, 51-56, and 123-128 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 6-9, 12-13, and 16-19 of copending Application No. 18/821,680 (herein after referred to as “’680”) in view of WO 2017/181148 A2 (previously cited on PTO-892; herein after referred to as “Swanson”) and Li et. al. (Expert Opin. Pharmacother., 2008, 9(13), 2305-2316; herein after referred to as "Li").
Claims 1, 14, 26, 29-30, 39-40, 51-56, and 123-126 are rendered obvious by the combined teachings of the prior art as discussed in the 103 section, the 103 being incorporated here. The addition of the patented claims of the above-listed reference patents over related subject matter only further supports this obviousness.
‘680 claims 1-2 disclose a variant ICOS Ligand (ICOSL) polypeptide, comprising an IgV domain or specific binding fragment thereof, an IgC domain or a specific binding fragment thereof, or both, wherein the variant ICOSL polypeptide comprises one or more amino acid modifications at one or more positions in an unmodified ICOSL or a specific binding fragment thereof corresponding to the recited positions, wherein the unmodified ICOSL comprises (i) the sequence of amino acids set forth in SEQ ID NO:32, (ii) a sequence of amino acids that has at least 95% sequence identity to SEQ ID NO:32; or (iii) a portion of the sequence of (i) or (ii) comprising an IgV domain or IgC domain or specific binding fragments thereof or both; ‘680 SEQ ID NO: 32 is a 100% match to instant SEQ ID NO: 1. ‘680 claim 6 discloses that the IgV domain or specific binding fragment thereof is the only ICOSL portion of the variant ICOSL polypeptide and claims 7-8 disclose a fusion protein comprising a variant ICOSL polypeptide of claim 1 and an Fc domain, wherein the Fc domain may have reduced effector function. ‘680 claim 9 discloses that the variant ICOSL polypeptide of claim 1 is a transmembrane immunomodulatory protein, wherein the variant ICOSL polypeptide further comprises a transmembrane domain and/or a cytoplasmic signaling domain. ‘680 claims 12-13 are drawn to nucleic acid molecules encoding the variant ICOSL polypeptide of claim 1 and an engineered cell thereof. ‘680 claim 16 discloses a pharmaceutical composition comprising the variant ICOSL polypeptide of claim 1, or a nucleic acid molecule thereof, and a pharmaceutically acceptable carrier. ‘680 claims 17-18 are drawn to methods of modulating immune responses comprising administering (i) the pharmaceutical composition of claim 16 or (ii) the engineered cell of claim 13, respectively, and claim 19 is drawn to a method of treatment comprising administering the pharmaceutical composition of claim 16. However, it is noted that ‘680 is not drawn to the instantly claims variant ICOSL polypeptides/fusion proteins nor preventing/reducing aGVHD of Grades II-IV that is refractory to immunosuppressants including corticosteroids or cyclosporine comprising administering a variant ICOSL fusion protein as instantly claimed. These deficiencies are addressed by the cited references, as provided by the teachings specified in the 103 section.
‘680, Swanson, and Li are considered to be analogous to the present invention as they are in the same field of ICOSL polypeptides/fusion polypeptides and/or immune modulation. Thus, it would have been obvious to one of ordinary skill in the art to modify the variant ICOSL polypeptides/fusion proteins, pharmaceutical compositions, and methods thereof of ‘680 to arrive at a method for treating (i.e., reducing) GVHD (which can include aGVHD) comprising administering a variant ICOSL fusion protein of the instantly claimed sequences in an amount from at or about 0.1 mg/kg to at or about 20 mg/kg, as suggested by Swanson, in cases of aGVHD, including (i) Grades II-IV and (ii) wherein said aGVHD is refractory to corticosteroids, as suggested by Li, because combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to modify the variant ICOSL polypeptides/fusion proteins, pharmaceutical compositions, and methods thereof of the reference patents based on the teachings of Swanson and Li to arrive at a method of treating aGVHD, including Grades II-IV, wherein said aGVHD is refractory to corticosteroids in order to more effectively treat aGVHD that cannot be controlled by typical first- and second-line therapies in order to improve patient outcomes, because Li specifically indicates that ICOS/ICOS-L blockade might be an especially attractive target for downregulating T-cell responses in GVHD once it has been initiated (emphasis added).
Similarly, claims 1, 14, 26, 29-30, 39-40, 51-56, and 123-126 are rejected on the ground of nonstatutory double patenting as being unpatentable over the pertinent claims of the U.S. Patents listed in the table below in view of WO 2017/181148 A2 (previously cited on PTO-892; herein after referred to as “Swanson”) and Li et. al. (Expert Opin. Pharmacother., 2008, 9(13), 2305-2316; herein after referred to as "Li"):
Patent Number
Brief Description of the Invention
Pertinent Claims
10882914
Variant ICOSL Polypeptides and Fusion Proteins Thereof
1-8, 12-15, 17-27, 30-36, 39-45
11613566
Variant ICOSL-Fc Fusion Protein and Pharmaceutical Composition Thereof
1-4
12110339
Variant ICOSL Polypeptides, Fusion Proteins, Pharmaceutical Compositions, Methods of Modulating Immune Responses, and Methods of Treatment Thereof
1-3, 5-8, 10-21
Claims 1, 14, 26, 29-30, 39-40, 51-56, and 123-126 are rendered obvious by the combined teachings of the prior art as discussed in the 103 section, the 103 being incorporated here. The addition of the patented claims of the above-listed reference patents over related subject matter only further supports this obviousness.
It is noted that the above-mentioned reference patents are all drawn to variant ICOSL polypeptides/fusion proteins, pharmaceutical compositions, and general methods of treatment/modulating immune responses thereof. However, it is noted that above-listed reference patents are not necessarily drawn to the instantly claims variant ICOSL polypeptides/fusion proteins nor preventing/reducing aGVHD of Grades II-IV that is refractory to immunosuppressants including corticosteroids or cyclosporine comprising administering a variant ICOSL fusion protein as instantly claimed. These deficiencies are addressed by the cited references, as provided by the teachings specified in the 103 section.
The reference patents, Swanson, and Li are considered to be analogous to the present invention as they are in the same field of ICOSL polypeptides/fusion polypeptides and/or immune modulation. Thus, it would have been obvious to one of ordinary skill in the art to modify the variant ICOSL polypeptides/fusion proteins, pharmaceutical compositions, and methods thereof of the reference patents to arrive at a method for treating (i.e., reducing) GVHD (which can include aGVHD) comprising administering a variant ICOSL fusion protein of the instantly claimed sequences in an amount from at or about 0.1 mg/kg to at or about 20 mg/kg, as suggested by Swanson, in cases of aGVHD, including (i) Grades II-IV and (ii) wherein said aGVHD is refractory to corticosteroids, as suggested by Li, because combining prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to modify the variant ICOSL polypeptides/fusion proteins, pharmaceutical compositions, and methods thereof of the reference patents based on the teachings of Swanson and Li to arrive at a method of treating aGVHD, including Grades II-IV, wherein said aGVHD is refractory to corticosteroids in order to more effectively treat aGVHD that cannot be controlled by typical first- and second-line therapies in order to improve patient outcomes, because Li specifically indicates that ICOS/ICOS-L blockade might be an especially attractive target for downregulating T-cell responses in GVHD once it has been initiated (emphasis added).
Conclusion
Claims 1, 14, 26, 29-30, 39-40, 51-56, and 123-126 are pending. Claims 1, 14, 26, 29-30, 39-40, 51-56, and 123-126 are rejected. No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/NELSON B MOSELEY II/Primary Examiner, Art Unit 1642