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 .
Priority
The instant application is claiming the benefit as a 35 U.S.C. 371 national phase application from, and claims priority to, International Application No. PCT/US2021/057352, filing date 10/29/2021, which claims the benefit of the prior-filed United States Provisional Patent Application Nos. 63/123,991 (filing date 12/10/2020) and 63/198,615 (filing date 10/29/2020).
Status of Application/Claims
The preliminary amendment, filed 12/12/2023, is acknowledged. Claims 6-12, 15-19, 21, 23-24, 27, 29-30, 32, 34-35, 37, 39-40, 42, and 44-46 are canceled. Claims 1, 3-5, 13-14, 20, 22, 26, 28, 31, 36, 38, 41, and 43 are amended. Claims 47-48 are new. Claims 1-5, 13-14, 20, 22, 25-26, 28, 361, 33, 36, 38, 41, 43, and 47-48 are currently pending and are examined on the merits herein.
Information Disclosure Statements
The information disclosure statements (IDSs) submitted on 12/12/2023 and 02/06/2024 have been fully considered by the examiner.
Specification
The use of the terms Biolegend, New England Biolabs, The Jackson Laboratory, ThermoFisher Scientific, BD Biosciences, Invitrogen, FlowJo, eBioscience, Molecular Devices, Albustix, Siemens, Novartis, Cremophor, Alza, and Nova Pharmaceuticals which are trade names or marks used in commerce, have been noted in this application. The terms should be in all caps wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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.
Hyperlinks are found on the following pages of the disclosure:
p.23, [0098]
“blast.ncbi.nlm.nih.gov” contains a prefix (underlined)
p.24, [0098]:
“www.ebi.ac.uk/Tools/psa” contains a prefix (underlined) and is not limited to the top-level domain (see bold)
p.24, [0100]:
“worldwideweb.gcg.com” contains a prefix (underlined)
p.24, [0101]:
“worldwideweb .ncbi .nlm.nih.gov.” contains a prefix (underlined)
Claim Objections
Claim 31 is objected to because of the following informalities: Claim 31 recites “The method of any one of claim 1…” which should be corrected to “The method of claim 1…”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claim 41 is 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 terms “at least seven fewer glycosylation,” “at least eight fewer glycosylation,” and “at least nine fewer glycosylation,” in claim 41 are relative terms which render the claims indefinite for the following reasons:
The terms are not defined by the claims, the specification does not provide a standard for ascertaining the requisite degrees, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear what glycosylation types and levels are being compared. That is, it is unclear which amino acid residues are considered to be “glycosylated” in the native IL-2Rα ECD protein SEQ ID NO: 1 being referenced when considering the comparison to truncated IL-2Rα protein SEQ ID NO: 3 as the instant disclosure provides no guidance on glycosylated residues and states that the “different glycosylation” can be achieved via mutation of glycosylation sites or at other amino acid residues that impact glycosylation sites (p.54-56, [0233 – 0245]).
For further examination, the claim is interpreted to include any known O- and/or N-glycosylation sites, provided by the prior art, in the scope of the claim. The prior art supports that there are six glycosylation sites for (human) IL-2Rα (i.e., SEQ ID NO: 1): 2 N-linked glycosylations at N70 and N89; and, 4 O-linked glycosylations at T218, T224, T229, and T237, wherein these positions correspond to the pre-processed form that contains a signal sequence. Thus, the claim is interpreted to mean that the method includes a fusion protein wherein the extracellular domain of the IL-2Rα has up to “at least six fewer glycosylations.” See UniProt. P01589 – ILRA_Human. Last updated 7/21/1986. p.5 (herein referred to as UniProt) and Miedel, et al. Structural analysis of recombinant soluble human interleukin-2 receptor. Biochemical and Biophysical Research Communications (1988), 154:1, p.374 (rIL-2Rα; herein referred to as Miedel).
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.
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 1-5, 13-14, 20, 22, 26, 28, 31, 33, 41, 43, and 47-48 are rejected under 35 U.S.C. 103 as being unpatentable over Struthers, et al. US20190300592A1 – Interleukin-2/Interleukin-2 receptor alpha fusion proteins and methods of use (publication date: 10/03/2019; effective filing date: 03/28/2018) herein referred to as Struthers; as evidenced by UniProt. P01589 – ILRA_Human. Last updated 7/21/1986. p.5, herein referred to as UniProt.
[AltContent: textbox (Mature human IL-2Rα ECD instant SEQ ID NO: 1 vs. Struthers SEQ ID NO: 7 (full)
[img-media_image1.png])]Struthers teaches IL-2/IL-2Rα fusion proteins and methods of use thereof (title; abstract; p.4, [0040]); and, wherein IL-2 comprises at least one fewer glycosylations and/or IL-2Rα extracellular domain comprises at least one fewer glycosylations, two fewer glycosylations, three fewer glycosylations, four fewer glycosylations, five fewer glycosylations, six fewer glycosylations, seven fewer glycosylations, eight fewer glycosylations, or at least nine fewer glycosylations compared to native IL-2Rα encoded by Struthers’ SEQ ID NO: 7, which aligns 100% with instant SEQ ID NO: 1 (title; abstract; p.1, [0007]; see alignment below for mature IL-2Rα ECD – i.e., no signal sequence):
[AltContent: textbox (Mature human IL-2 instant SEQ ID NO: 2 vs. Struthers SEQ ID NO: 2
[img-media_image2.png])]Struthers additionally teaches an IL-2 polypeptide that has at least one fewer glycosylation compared to native IL-2 of SEQ ID NO: 2. Struthers’ IL-2 SEQ ID NO: 2 aligns 100% with instant SEQ ID NO: 2 (p.1, [0007]; see alignment below):
Additionally, Struthers teaches that any of the glycosylation sites of the fusion proteins disclosed herein can be removed by enzymatic or chemical deglycosylation (p.33, [0295]). Further, Struthers teaches fusion proteins wherein the IL-2Rα extracellular domain is encoded by SEQ ID NO: 12 (i.e., amino acids 22-202 of pre-processed IL-2Rα), which overlaps with truncated instant amino acid SEQ ID NO: 3 at 100% identity (i.e., amino acids 1-191 of mature IL-2Rα); thus, Struthers’ SEQ ID NO: 12 and the instant SEQ ID NO: 3 both lack the 4 O-linked glycosylation sites that correspond to amino acid positions T218, T224, T229, and T237 of native (unprocessed) IL-2Rα (i.e., at least one, two, three, and four fewer glycosylations; as evidenced by UniProt; see alignments below; white arrows indicate sites of O-linked glycosylation in the full pre-processed protein that are missing in the truncated protein):
[AltContent: textbox (Mature truncated human IL-2Rα ECD instant SEQ ID NO: 3 vs. UniProt P01589 – top = truncated, bottom = full length
[img-media_image3.png])]
Additionally, Struthers teaches that IL-2 is a potent T cell growth factor that promotes immune responses and is approved by the FDA for use in patients with melanoma and renal cell carcinoma; but that response rates were low in these and other cancers and the therapy was accompanied by sever toxicity (p.1, [0005]). Struthers teaches that low-dose IL-2 has been used to selectively boost tolerance to suppress unwanted immune responses associated with autoimmune-like attack of self-tissues; and, selectively promoted key activities of Tregs but not T effector cells and that treatment of mice with low levels of IL-2 prevented autoimmunity (p.1, [0006]. Struthers teaches that low-dose IL-2 therapy is safe but has important drawbacks including a short half-life in vivo, which limits its efficacy, and toxicity at high doses (p.1, [0006]). Struthers teaches that the IL-2/IL-2Rα fusion proteins have one or more of the following properties/activities: 1) increasing activity of regulatory T cells (Tregs) and/or increasing immune tolerance in low dose IL-2 based therapies; 2) increasing immune response and memory in higher dose therapies; 3) increasing IL-2 availability when compared to recombinant IL-2; and/or 4) increasing persistent IL-2 stimulation of IL-2R bearing lymphocytes in vivo (p.32, [0282]). Struthers also teaches that truncated versions of IL-2/CD25 (i.e., IL-2/IL-2Rα) have improved stability against aggregation (p.57, [0477]; Example 3).
Struthers teaches that administration of the fusion protein can be used to treat subjects where modulation of the immune response is desirable, for treatment of cancer, and in subjects bearing a virus (i.e., infection; p.27, [0371], [0377]). Struthers teaches that the fusion proteins can be administered for treatment of patients with inflammatory or autoimmune diseases, chronic graft versus host disease, transplant rejection reactions, and other conditions where the goal is to suppress self-reactivity (p.48, [0386]; p.51, section 7.7.2.2). Struthers further teaches that treatment wherein the inflammatory or autoimmune disease is type 1 diabetes, multiple sclerosis, rheumatoid arthritis, celiac disease, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, juvenile idiopathic arthritis, Crohn’s disease, ulcerative colitis or systemic sclerosis, psoriasis, alopecia areata, HCV-induced vasculitis, Sjogren’s syndrome, pemphigus, ankylosing spondylitis, Bechet’s Disease, Wegener’s Granulomatosis, Takayasu’s Disease, autoimmune hepatitis, sclerosing cholangitis, Gougerot-Sjogren, and macrophage activation syndrome (p.51, [0412] and section 7.7.2.2).
Struthers teaches that the fusion protein can be administered via a topical, epidermal, mucosal, intranasal, oral, vaginal, rectal, sublingual, intravenous, intraperitoneal, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intrascapsular, intraorbital, intracardiac, intradermal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, or intrasternal route (p.48, [0384]). Struthers teaches treatment with IL-2/IL-2Rα fusion protein wherein administration occurs every third day on day 0, 3, and 6 (i.e., at least about one day, at least about two days, or at least about 3 days dosing interval; i.e., the dosing interval is the same throughout the doses; p.61, [0486]).
Struthers also teaches that the fusion protein can be co-administered with a second agent that can include one or more therapeutic agents that may be cytotoxic agents, radiotoxic agents, or immunosuppressive agents; anti-neoplastic agents; small molecule drugs, antibodies or antigen binding protein thereof; immune checkpoint inhibitors or stimulators; alkylating agents; antimetabolites; chemotherapies; hormones and steroids, including prednisolone (p.52, [0423] – 56, [0464]; section 7.7.2.5). Struthers teaches that the secondary hormone or steroid agent can be administered prior to or in conjunction with the fusion protein (p.55, [0460]); and, administered concurrently or sequentially (p.55, [0461]); and, that the secondary agent can be administered as desired (p.55, [0460]).
Regarding dosages, Struthers teaches single dose subcutaneous administration of 0.075 mg/kg fusion protein to cynomolgus monkeys (p.4, [0049]; Fig.5; Table 14); and, teaches that the average body weight for the monkeys is 7.8 kg (p.58, [0480]). This would result in administration of approximately 0.585 mg to the subject (i.e., a dose from about 0.1 mg to about 9 mg; i.e., between about 0.3 mg to about 9 mg; i.e., between about 0.1 mg to about 3 mg; i.e., between about 0.1 mg to about 1 mg; i.e., between about 0.3 mg to about 6 mg; i.e., about 5 mg; i.e., about 6 mg). Struthers also discusses both weight-based and flat dosages. Struthers provides an example weight-based dosage in humans of 3 mg/kg IL-2/IL-2Rα fusion protein for a patient body weight range of 60 kg to 100 kg, which would result in 180 mg to 300 mg (i.e., a dose greater than about 9 mg; p.12, [0128]); and, provides an example of a flat dose of 480 mg of IL-2/IL-2Rα fusion protein (i.e., a dose greater than about 9 mg; p.12, [0129]).
Struthers does not specifically teach a single embodiment or example wherein the subjects treated (i.e., monkeys or mice) with the IL-2/IL-2Rα with modified glycosylation have a stated disease or disorder (instant claim 1); or, wherein one of the two or more doses is administered intravenously and at least one of the two or more doses is administered subcutaneously (instant claim 28).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to combine the teachings of Struthers by using the fusion protein comprising an IL-2 polypeptide with at least one fewer glycosylation and an IL-2Rα ECD with at least one, two, three, four, five, six, seven, eight, or nine fewer glycosylations wherein the dose is from about 0.1 mg to about 9 mg or greater than about 9 mg (as taught by Struthers) to treat in a method of treating a disease or disorder such as an inflammatory disease, autoimmune disease, infectious disease, or cancer (also taught by Struthers), to arrive at the instantly claimed invention, because the combination of Struthers’ teachings suggests that the IL-2/IL-2Rα fusion protein can be used in a method of treatment for the aforementioned diseases. One would also be motivated to do so because Struthers teaches that the fusion protein with truncated IL-2Rα with fewer glycosylations affords greater protein stability and increased Treg activation.
Regarding instant claims 4-5, 14, and 20, the combination of Struthers’ teachings does not explicitly teach the following dosages: between about 3 mg to about 9 mg, between about 6 mg to about 9 mg, between about 0.1 mg to about 0.3 mg, or between about 1 mg to about 3 mg (instant claim 4); about 0.1 mg, about 0.3 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 7 mg, about 8 mg, or about 9 mg (instant claim 5); between about 1 mg to about 8 mg, between about 3 mg to about 8 mg, between about 6 mg to about 8 mg, between about 1 mg to about 6 mg, between about 1 mg to about 3 mg, or between about 3 mg to about 6 mg (instant claim 14); or, about 0.1 mg, about 0.3mg,_about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, or about 8 mg (instant claim 20). However, the dosage ranges for administration of the fusion protein to ‘a subject’ taught by Struthers ranges from 0.585 mg (for monkey) to 480 mg (for human). Thus, the dosage ranges of 0.1 mg to 9 mg and doses of greater than 9 mg overlaps substantially with what the prior art teaches.
Thus, it would have also been prima facie obvious for one of ordinary skill in the art before the effective filing date to use the dosages taught and to use routine optimization to arrive at the dosages of instant claims 4-5, 14, and 20 that are not explicitly taught by Struthers. Further, Struthers teaches that weight-based dosages for treatment, which would obviously require adjustments in dosages that may vary slightly from those explicitly taught by Struthers. See MPEP 2144.05.
Regarding instant claim 28, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of Struthers to include both a subcutaneous dose and an intravenous dose (taught by Struthers) for routes of administration for at least two or more of the dose, to arrive at the instantly claimed invention, because Struthers also teaches that subjects were treated on days 0, 3, and 6 and the combination of prior art routes of administration results in a predictable result of treating a disease or disorder in the subject. One of ordinary skill in the art would have a reasonable expectation of success because Struthers teaches that subjects can be treated via various routes of administration and specifically teaches that intravenous and subcutaneous routes of administration were used in (murine) subjects.
Claims 1, 22, 25, 31, and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Struthers and as applied to claims 1 and 22 above; and, further in view of Boyman. NCT03312335 – Low-dose interleukin-2 for treatment of systemic lupus erythematosus (Charact-IL-2). National Center for Biothenology Information, National Library of Medicine. Internet – Clinicaltrials.gov. Posted 10/17/2007 herein referred to as Boyman.
The combination of teachings by Struthers teaches the method of treating a infectious disease or immune-related disease by administration of an IL-2/IL-2Rα fusion protein wherein the IL-2 and IL-2Rα have fewer glycosylations relative to the native proteins, wherein the dose is from about 0.1 mg to about 9 mg, and wherein two or more of the dose are administered at a dosing interval between two doses is at least about one, two, or three days, as described in detail above for instant claims 1, 22, and 31. Struthers also teaches that the fusion protein can be administered with a secondary agent that can be a steroid, including prednisolone that can be administered as desired prior to, in conjunction, concurrently, or sequentially with the fusion protein, as described in detail above.
Struthers does not teach a dosing interval that is about three weeks (instant claim 25); or, that the steroid treatment is specifically a corticosteroid treatment (instant claim 36).
Boyman teaches low-dose IL-2 for treatment of systemic lupus erythematosus (SLE) and that SLE is an autoimmune disease characterized by a numerical and functional deficit of regulatory T cells (Tregs). Boyman teaches that Tregs are highly dependent of IL-2 and that low doses of IL-2 leads to markedly increased numbers and improved functionality of Treg cells in mice and humans (p.1, para.1). Boyman also teaches subcutaneous injection of IL-2 once daily in 5-day courses with dosing every three weeks for a total of four cycles (p.4, Arms and Interventions table). Boyman teaches that the primary outcome of the study is an increase in percentage of Tregs (p.4, Primary Outcome Measures table) and a secondary outcome of measuring soluble CD25 (IL-2Rα in serum of SLE patients (p.4, Secondary Outcome Measures table). Additionally, Boyman teaches corticosteroid treatment given at a stable dose for at least 4 weeks prior to treatment (p.3, para.1).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of Struthers with the teachings of Boyman by treating subjects having a disease or disorder such as SLE with an IL-2/IL-2Rα fusion protein with modified glycosylation (as taught by Struthers) by treating patients with a dosing interval is about three weeks (as taught by Boyman), to arrive at the instantly claimed invention, because the combination of prior art elements according to known methods results in a predictable result of treating SLE by increasing activation of Tregs. One of ordinary skill in the art would have a reasonable expectation of success because both Struthers and Boyman teach treatments comprising subcutaneous administration of IL-2-containing protein for activation of Tregs for the treatment of SLE. One of ordinary skill in the art would also have a reasonable expectation of success because Struthers teaches that a disadvantage of low-dose IL-2 is short half-life, but that the IL-2/IL-2Rα fusion protein that has modified glycosylation provides for improved protein stability. Thus, one would be motivated to improve a method of treatment for SLE wherein the dosage interval is every three weeks by using a more stable IL-2/IL-2Rα fusion protein construct for Treg activation.
It would also have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Struthers with the teachings of Boyman by using a corticosteroid (taught by Boyman) steroid (taught by Struthers and Boyman) as a second agent (taught by Struthers) in the treatment method by administering the corticosteroid (taught by Boyman) prior to administrating the IL-2/IL-2Rα fusion protein (taught by Struthers). One of ordinary skill in the art would have a reasonable expectation of success because both Struthers and Boyman teach treatment with IL-2-containing proteins in combination with steroids in methods of treating SLE.
Claims 1, 31, 36 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Struthers and Boyman, as applied to claims 1, 31, and 36 above; and, further in view of Orapred ODT®. Highlights of prescribing information. July 2010. FDA: NDA 21-959/S-004, p.1-12 herein referred to as FDA.
The combination of teachings by Struthers and Boyman teaches the method of treating a disease or disorder by administration of an IL-2/IL-2Rα fusion protein wherein the IL-2 and IL-2Rα have fewer glycosylations relative to the native proteins, wherein the dose is from about 0.1 mg to about 9 mg, and wherein treatment of an infectious disease or an immune-mediated disease further comprises administering a steroid, as described in detail above for instant claims 131, and 36; and, wherein a second agent corticosteroid that is prednisolone that can be administered as desired prior to, in conjunction, concurrently, or sequentially with the fusion protein, as described in detail above. prednisolone
Struthers does not teach that the steroid/prednisolone is specifically a corticosteroid (instant claim 36); or that the corticosteroid is administered orally (instant claim 38).
FDA teaches prescribing information for prednisolone (i.e. Orapred ODT) and teaches that prednisolone is a corticosteroid indicated as an anti-inflammatory or immunosuppressive agent used for treatment of various conditions including allergic conditions, dermatologic diseases, endocrine conditions, gastrointestinal disease, hematologic disease, neoplastic conditions, nervous system conditions, ophthalmic conditions, conditions related to organ transplantation, pulmonary disease, renal conditions, rheumatologic conditions including SLE, and infectious disease (p.1, Indications and Usage; p.3-4). FDA provides dosage information for oral use and warnings and precautions (p.4). FDA further teaches clinical pharmacology for prednisolone with inhibits inflammatory processes (p.10, section 12.1).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of Struthers and Boyman with the teachings of FDA by using oral prednisolone (taught by FDA corticosteroid (taught by Stuthers and FDA) as the steroid administered prior to, sequentially or concurrently with the IL-2/IL-2Rα fusion protein (as taught by Struthers), to arrive at the instantly claimed invention, because the combination of prior art elements according to known methods results in a predictable result. One of ordinary skill would have a reasonable expectation of success because Struthers teaches that a steroid such as prednisolone can be the secondary agent administered and FDA teaches that prednisolone is a corticosteroid. Further, one would be motivated to use oral prednisolone because FDA teaches that oral prednisolone tablets can be used to inhibit inflammatory processes and for treatment of patients with autoimmune disease such as SLE.
Double Patenting
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.
Co-Pending Application 18/977,416
Claims 1-5, 13-14, 20, 22, 25-26, 28, 361, 33, 36, 38, 41, 43, and 47-48 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 11, 96, and 100-101 of copending Application No. 18/977,416 (herein referred to as App’416); and, in further view of Struthers, Boyman, and FDA.
App’416 teaches a fusion protein comprising a first polypeptide of IL-2 having at least one fewer glycosylations than native IL-2 and a second polypeptide of IL-2Rα having at least one fewer glycosylations than native IL-2Rα (App’416 claim 1; instant claims 1, 47, and 48); wherein the IL-2 shares identity with SEQ ID NO: 2 (App’416 claim 4; instant claims 1, 41, 43, 47, and 48, and instant SEQ ID NO: 2); wherein the IL-2Rα shares identity with SEQ ID NO: 12 (App’416 claims 4 and 11; instant claims 1, 41, 43, 47, and 48, and instant SEQ ID NOs 1 and 3). App’416 teaches administration of the fusion protein for a method of treating a disease or disorder (App’416 claim 96; instant claims 1 and 47) wherein the disorder is an inflammatory, autoimmune (i.e., immune-related), or infectious disease/disorder (App’416 claims 99-101; instant claims 31 and 33).
App’416 does not teach a method of treating a disease or disorder wherein the fusion protein dose is about 0.1 mg to about 9 mg (instant claim 1) or greater than about 9 mg (instant claim 47); a method of fusion protein administration for increasing Treg activity wherein the dose is from about 0.1 mg to about 9 mg (instant claim 48); routes of administration (instant claim 2); intravenous administration (instant claim 3); subcutaneous administration (instant claim 13); dosages for administration (instant claims 4-5, 14, and 20); dosing intervals of at least about one, two, or three days between two or more of a dose (instant claim 22); a dosing interval of about three weeks (instant claim 25); a method wherein at least one dose is administered intravenously and at least one dose is administered subcutaneously (instant claim 28); a method further comprising administration of a corticosteroid (instant claim 36); or, corticosteroid administration that is oral and that is given prior to (i.e., before), sequentially, or concurrently with administration of the fusion protein (instant claim 38).
Struthers teaches IL-2/IL-2Rα fusion proteins and methods of use thereof (title; abstract; p.4, [0040]); and, wherein IL-2 or IL-2Rα extracellular domain comprises at least one fewer glycosylations, two fewer glycosylations, three fewer glycosylations, four fewer glycosylations, five fewer glycosylations, six fewer glycosylations, seven fewer glycosylations, eight fewer glycosylations, or at least nine fewer glycosylations compared to native IL-2Rα encoded by Struthers’ SEQ ID NO: 7, which aligns 100% with instant SEQ ID NO: 1 (title; abstract; p.1, [0007]; see alignment above for mature IL-2Rα ECD – i.e., no signal sequence).
Struthers additionally teaches an IL-2 polypeptide that has at least one fewer glycosylation compared to native IL-2 of SEQ ID NO: 2, which aligns 100% with instant SEQ ID NO: 2 (p.1, [0007]; see alignment above).
Further, Struthers teaches fusion proteins wherein the IL-2Rα extracellular domain is encoded by SEQ ID NO: 12 (i.e., amino acids 22-202 of pre-processed IL-2Rα), which overlaps with truncated instant amino acid SEQ ID NO: 3 at 100% identity (i.e., amino acids 1-191 of mature IL-2Rα); thus, Struthers’ SEQ ID NO: 12 and the instant SEQ ID NO: 3 both lack the 4 O-linked glycosylation sites that correspond to amino acid positions T218, T224, T229, and T237 of native (unprocessed) IL-2Rα (i.e., at least four fewer glycosylations; as evidenced by UniProt; see alignments above; white arrows indicate sites of O-linked glycosylation in the full pre-processed protein that are missing in the truncated protein).
Additionally, Struthers teaches that IL-2 is a potent T cell growth factor that promotes immune responses and is approved by the FDA for use in patients with melanoma and renal cell carcinoma; but that response rates were low in these and other cancers and the therapy was accompanied by sever toxicity (p.1, [0005). Struthers teaches that low-dose IL-2 has been used to selectively boost tolerance to suppress unwanted immune responses associated with autoimmune-like attack of self-tissues; and, selectively promoted key activities of Tregs but not T effector cells and that treatment of mice with low levels of IL-2 prevented autoimmunity (p.1, [0006]. Struthers teaches that low-dose IL-2 therapy is safe but has important drawbacks including a short half-life in vivo, which limits its efficacy, and toxicity at high doses (p.1, [0006]). Struthers teaches IL-2/IL-2Rα fusion proteins that have one or more of the following properties/activities: 1) increasing activity of regulatory T cells (Tregs) and/or increasing immune tolerance in low dose IL-2 based therapies; 2) increasing immune response and memory in higher dose therapies; 3) increasing IL-2 availability when compared to recombinant IL-2; and/or 4) increasing persistent IL-2 stimulation of IL-2R bearing lymphocytes in vivo (p.32, [0282]). Struthers also teaches that truncated versions of IL-2/CD25 (i.e., IL-2/IL-2Rα) have improved stability against aggregation (p.57, [0477]; Example 3).
Struthers teaches that administration of the fusion protein can be used to treat subjects where modulation of the immune response is desirable, for treatment of cancer, and in subjects bearing a virus (i.e., infection; p.27, [0371], [0377]). Struthers teaches that the fusion proteins can be administered for treatment of patients with inflammatory or autoimmune diseases, chronic graft versus host disease, transplant rejection reactions, and other conditions where the goal is to suppress self-reactivity (p.48, [0386]; p.51, section 7.7.2.2). Struthers further teaches that treatment wherein the inflammatory or autoimmune disease is type 1 diabetes, multiple sclerosis, rheumatoid arthritis, celiac disease, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, juvenile idiopathic arthritis, Crohn’s disease, ulcerative colitis or systemic sclerosis, psoriasis, alopecia areata, HCV-induced vasculitis, Sjogren’s syndrome, pemphigus, ankylosing spondylitis, Bechet’s Disease, Wegener’s Granulomatosis, Takayasu’s Disease, autoimmune hepatitis, sclerosing cholangitis, Gougerot-Sjogren, and macrophage activation syndrome (p.51, [0412] and section 7.7.2.2).
Struthers teaches that the fusion protein can be administered via a topical, epidermal, mucosal, intranasal, oral, vaginal, rectal, sublingual, intravenous, intraperitoneal, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intrascapsular, intraorbital, intracardiac, intradermal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, or intrasternal route (p.48, [0384]). Struthers teaches treatment with IL-2/IL-2Rα fusion protein wherein administration occurs every third day on day 0, 3, and 6 (i.e., at least about one day, at least about two days, or at least about 3 days dosing interval; i.e., the dosing interval is the same throughout the doses; p.61, [0486]).
Struthers also teaches that the fusion protein can be co-administered with a second agent that can include one or more therapeutic agents that may be cytotoxic agents, radiotoxic agents, or immunosuppressive agents; anti-neoplastic agents; small molecule drugs, antibodies or antigen binding protein thereof; immune checkpoint inhibitors or stimulators; alkylating agents; antimetabolites; chemotherapies; hormones and steroids, including prednisolone (p.52, [0423] – 56, [0464]; section 7.7.2.5). Struthers teaches that the secondary hormone or steroid agent can be administered prior to or in conjunction with the fusion protein (p.55, [0460]); and, administered concurrently or sequentially (p.55, [0461]); and, that the secondary agent can be administered as desired (p.55, [0460]).
Regarding dosages, Struthers teaches single dose subcutaneous administration of 0.075 mg/kg fusion protein to cynomolgus monkeys (p.4, [0049]; Fig.5; Table 14); and, teaches that the average body weight for the monkeys is 7.8 kg (p.58, [0480]). This would result in administration of approximately 0.585 mg to the subject (i.e., a dose from about 0.1 mg to about 9 mg; i.e., between about 0.3 mg to about 9 mg; i.e., between about 0.1 mg to about 3 mg; i.e., between about 0.1 mg to about 1 mg; i.e., between about 0.3 mg to about 6 mg; i.e., about 5 mg; i.e., about 6 mg). Struthers also discusses both weight-based and flat dosages for human patients. Struthers provides an example weight-based dosage of 3 mg/kg IL-2/IL-2Rα fusion protein for a patient body weight range of 60 kg to 100 kg, which would result in 180 mg to 300 mg (i.e., a dose greater than about 9 mg; p.12, [0128]); and, provides an example of a flat dose of 480 mg of IL-2/IL-2Rα fusion protein (i.e., a dose greater than about 9 mg; p.12, [0129]).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to combine the teachings of App’416 with the teachings of Struthers by using the IL-2/IL-2Rα fusion protein taught by App’416 for the method of increasing Treg activity using the dosages, routes of administration, and dosing intervals taught by Struthers, in order to arrive at the instantly claimed invention, because the combination of teachings by App’416 and Struthers according to known methods results in predictable results. One of ordinary skill in the art would have a reasonable expectation of success because the amino acid sequence identities for the IL-2 and IL-2Rα proteins of App’416 and Struthers are 100% identical. Further, treating a disease or disorder (including infectious diseases and immune-mediated disorders) and increasing Treg activity describe inherent properties of the known fusion protein that do not render the claim patentably new (see MPEP 2112). The instant fusion protein necessarily possesses the same properties as the fusion protein taught by both App’416 and Struthers. Thus, the combination of teachings provided by App’416 and Struthers teaches instant claims 1, 31, 33, and 47-48 based on inherent structure/function properties.
The combination of App’416 and Struthers does not specifically teach that the subjects treated (i.e., monkeys or mice) with the IL-2/IL-2Rα with modified glycosylation have a stated disease or disorder (instant claim 1); or, wherein one of the two or more doses is administered intravenously and at least one of the two or more doses is administered subcutaneously (instant claim 28).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of App’416 with the additional teachings of Struthers by using the fusion protein comprising an IL-2 polypeptide with at least one fewer glycosylation and an IL-2Rα ECD with at least one, two, three, four, five, six, seven, eight, or nine fewer glycosylations wherein the dose is from about 0.1 mg to about 9 mg or greater than about 9 mg (as taught by Struthers) to treat in a method of treating a disease or disorder such as an inflammatory disease, autoimmune disease, infectious disease, or cancer (taught by App’416 and Struthers), to arrive at the instantly claimed invention, because the combination of teachings by App’416 and Struthers’ suggests that the IL-2/IL-2Rα fusion protein can be used in a method of treatment for the aforementioned diseases. One would also be motivated to do so because Struthers teaches that the fusion protein with truncated IL-2Rα with fewer glycosylations affords greater protein stability and increased Treg activation.
Regarding instant claims 4-5, 14, and 20, the combination of App’416 and Struthers’ teachings does not explicitly teach the following dosages: between about 3 mg to about 9 mg, between about 6 mg to about 9 mg, between about 0.1 mg to about 0.3 mg, or between about 1 mg to about 3 mg (instant claim 4); about 0.1 mg, about 0.3 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 7 mg, about 8 mg, or about 9 mg (instant claim 5); between about 1 mg to about 8 mg, between about 3 mg to about 8 mg, between about 6 mg to about 8 mg, between about 1 mg to about 6 mg, between about 1 mg to about 3 mg, or between about 3 mg to about 6 mg (instant claim 14); or, about 0.1 mg, about 0.3mg,_about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, or about 8 mg (instant claim 20). However, the dosage ranges for administration of the fusion protein to ‘a subject’ taught by Struthers ranges from 0.585 mg (for monkey) to 480 mg (for human). Thus, the dosage ranges of 0.1 mg to 9 mg and doses of greater than 9 mg overlaps substantially with what the prior art teaches.
Thus, it would have also been prima facie obvious for one of ordinary skill in the art before the effective filing date to use the dosages taught and to use routine optimization to arrive at the dosages of instant claims 4-5, 14, and 20 that are not explicitly taught by the combination of App’416 and Struthers. Further, Struthers teaches that weight-based dosages for treatment, which would obviously require adjustments in dosages that may vary slightly from those explicitly taught by Struthers. See MPEP 2144.05.
Regarding instant claim 28, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the combination of teachings of App’416 and Struthers to include both a subcutaneous dose and an intravenous dose (taught by Struthers) for routes of administration for at least two or more of the dose, to arrive at the instantly claimed invention, because Struthers also teaches that subjects were treated on days 0, 3, and 6 and the combination of prior art routes of administration results in a predictable result of treating a disease or disorder in the subject. One of ordinary skill in the art would have a reasonable expectation of success because Struthers teaches that subjects can be treated via various routes of administration and specifically teaches that intravenous and subcutaneous routes of administration were used in (murine) subjects.
The combination of teachings by App’416 and Struthers teaches the method of treating infectious disease or immune-related disease by administration of an IL-2/IL-2Rα fusion protein wherein the IL-2 and IL-2Rα have fewer glycosylations relative to the native proteins, wherein the dose is from about 0.1 mg to about 9 mg, and wherein two or more of the dose are administered at a dosing interval between two doses is at least about one, two, or three days, as described in detail above for instant claims 1, 22, and 31. The combination of App’416 and Struthers also teaches that the fusion protein can be administered with a secondary agent that can be a steroid, including prednisolone that can be administered as desired prior to, in conjunction, concurrently, or sequentially with the fusion protein, as described in detail above.
The combination of teachings by App’416 and Struthers does not teach a dosing interval that is about three weeks (instant claim 25); or, that the steroid treatment is specifically a corticosteroid treatment (instant claim 36).
Boyman teaches low-dose IL-2 for treatment of systemic lupus erythematosus (SLE) and that SLE is an autoimmune disease characterized by a numerical and functional deficit of regulatory T cells (Tregs). Boyman teaches that Tregs are highly dependent of IL-2 and that low doses of IL-2 leads to markedly increased numbers and improved functionality of Treg cells in mice and humans (p.1, para.1). Boyman also teaches subcutaneous injection of IL-2 once daily in 5-day courses with dosing every three weeks for a total of four cycles (p.4, Arms and Interventions table). Boyman teaches that the primary outcome of the study is an increase in percentage of Tregs (p.4, Primary Outcome Measures table) and a secondary outcome of measuring soluble CD25 (IL-2Rα in serum of SLE patients (p.4, Secondary Outcome Measures table). Additionally, Boyman teaches corticosteroid treatment given at a stable dose for at least 4 weeks prior to treatment (p.3, para.1).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of App’416 and Struthers with the teachings of Boyman by treating subjects having a disease or disorder such as SLE with an IL-2/IL-2Rα fusion protein with modified glycosylation (as taught by App’416 and Struthers) by treating patients with a dosing interval of about three weeks (as taught by Boyman), to arrive at the instantly claimed invention, because the combination of prior art elements according to known methods results in a predictable result of treating SLE by increasing activation of Tregs. One of ordinary skill in the art would have a reasonable expectation of success because both Struthers and Boyman teach treatments comprising subcutaneous IL-2-comprising protein administration for activation of Tregs for the treatment of SLE. One of ordinary skill in the art would also have a reasonable expectation of success because Struthers teaches that a disadvantage of low-dose IL-2 is short half-life, but that the IL-2/IL-2Rα fusion protein that has modified glycosylation provides for improved protein stability. Thus, one would be motivated to improve a method of treatment wherein the dosage interval is every three weeks by using a more stable IL-2/IL-2Rα construct for Treg activation. It would also have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of App’416 and Struthers with the teachings of Boyman by using a corticosteroid (taught by Boyman) steroid (taught by Struthers and Boyman) as a second agent (taught by Struthers) in the treatment method by administering the corticosteroid (taught by Boyman) prior to administrating the IL-2/IL-2Rα fusion protein (taught by Struthers). One of ordinary skill in the art would have a reasonable expectation of success because both Struthers and Boyman teach treatment with IL-2-containing proteins in combination with steroids in methods of treating SLE.
The combination of teachings by App’416, Struthers, and Boyman does not teach that the steroid/prednisolone is specifically a corticosteroid (instant claim 36); or that the corticosteroid is administered orally (instant claim 38).
FDA teaches prescribing information for prednisolone (i.e. Orapred ODT) and teaches that prednisolone is a corticosteroid indicated as an anti-inflammatory or immunosuppressive agent used for treatment of various conditions including allergic conditions, dermatologic diseases, endocrine conditions, gastrointestinal disease, hematologic disease, neoplastic conditions, nervous system conditions, ophthalmic conditions, conditions related to organ transplantation, pulmonary disease, renal conditions, rheumatologic conditions including SLE, and infectious disease (p.1, Indications and Usage; p.3-4). FDA provides dosage information for oral use and warnings and precautions (p.4). FDA further teaches clinical pharmacology for prednisolone with inhibits inflammatory processes (p.10, section 12.1).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of App’416, Struthers, and Boyman with the teachings of FDA by using oral prednisolone corticosteroid (taught by FDA) as the steroid administered prior to, sequentially or concurrently with the IL-2/IL-2Rα fusion protein (as taught by App’416 and Struthers), to arrive at the instantly claimed invention, because the combination of prior art elements according to known methods results in a predictable result. One of ordinary skill would have a reasonable expectation of success because Struthers teaches that a steroid such as prednisolone can be the secondary agent administered and FDA teaches that prednisolone is an oral corticosteroid. Further, one would be motivated to use oral prednisolone because FDA teaches that oral prednisolone tablets can be used to inhibit inflammatory processes and for treatment of patients with autoimmune disease such as SLE.
This is a provisional nonstatutory double patenting rejection.
Co-Pending Application 19/031,056
Claims 1-5, 13-14, 20, 22, 25-26, 28, 31, 33, 36, 38, 41, 43, and 47-48 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 96, 110, and 115 of copending Application No. 19/031,056 (herein referred to as App’056); and, in further view of Struthers, Boyman, and FDA.
App’056 teaches a fusion protein comprising a first polypeptide of IL-2 and a second polypeptide of IL-2Rα of SEQ ID NOs: 138-142, which are all truncated proteins lacking the four O-linked glycosylation amino acid residues (see sequence comparison below; instant SEQ ID NO: 1 C-terminus comprising four O-linked glycosylation sites is bolded and absent in App’056 SEQ ID NOs: 138-142). Thus, App’056 teaches a fusion polypeptide having at least one, two three, and four fewer glycosylations than native IL-2Rα (App’056 claim 1; instant claims 1, 41, 47, and 48). App’056 also teaches that the fusion proteins that are deglycosylated enzymatically of chemically (App’056 claim 59; instant claims 1 and 47-48). App’056 teaches administration of an effective amount of a pharmaceutical composition comprising the fusion protein (App’056 claim 96; instant claims 1-5, 13-14, 20, 22, 25-26, 28, 31, 33, 36, 38, 41, 43, and 47-48). App’056 teaches a method comprising further administering to the subject a second agent (App’056 claim 110; instant claims36 and 38); and, App’056 teaches that the fusion protein can be administered via various routes of administration, including intravenous and subcutaneous routes (App’056 claim 115; instant claims 2-3 and 13).
App’056 does not teach a method of administering the fusion protein for treating a disease or disorder (instant claims 1 and 47); a method for increasing Tregs (instant claim 48); wherein the fusion protein dose is about 0.1 mg to about 9 mg (instant claims 1 and 47) or greater than about 9 mg (instant claim 47); a method of fusion protein administration for increasing Treg activity wherein the dose is from about 0.1 mg to about 9 mg (instant claim 48); dosages for administration (instant claims 4-5, 14, and 20); dosing intervals of at least about one, two, or three days between two or more of a dose (instant claim 22); a dosing interval of about three weeks (instant claim 25); a
[AltContent: textbox (Comparison of instant SEQ ID NO: 1 vs. App’056 IL-2Rα SEQ ID NOs: 138-142. C-terminal tail with four O-linked glycosylations in bold with O-linked glycosylation sites underlined; additional differing amino acids outside C-terminal region are also underlined.
[img-media_image4.png])]
method wherein at least one dose is administered intravenously and at least one dose is administered subcutaneously (instant claim 28); a method further comprising administration of a corticosteroid as the second agent (instant claim 36); or, a second agent corticosteroid administration that is oral and that is given prior to (i.e., before), sequentially, or concurrently with administration of the fusion protein (instant claim 38).
Struthers teaches IL-2/IL-2Rα fusion proteins and methods of use thereof (title; abstract; p.4, [0040]); and, wherein IL-2 or IL-2Rα extracellular domain comprises at least one fewer glycosylations, two fewer glycosylations, three fewer glycosylations, four fewer glycosylations, five fewer glycosylations, six fewer glycosylations, seven fewer glycosylations, eight fewer glycosylations, or at least nine fewer glycosylations compared to native IL-2Rα encoded by Struthers’ SEQ ID NO: 7, which aligns 100% with instant SEQ ID NO: 1 (title; abstract; p.1, [0007]; see alignment above for mature IL-2Rα ECD – i.e., no signal sequence).
Struthers additionally teaches an IL-2 polypeptide that has at least one fewer glycosylation compared to native IL-2 of SEQ ID NO: 2, which aligns 100% with instant SEQ ID NO: 2 (p.1, [0007]; see alignment above).
Further, Struthers teaches fusion proteins wherein the IL-2Rα extracellular domain is encoded by SEQ ID NO: 12 (i.e., amino acids 22-202 of pre-processed IL-2Rα), which overlaps with truncated instant amino acid SEQ ID NO: 3 at 100% identity (i.e., amino acids 1-191 of mature IL-2Rα); thus, Struthers’ SEQ ID NO: 12 and the instant SEQ ID NO: 3 both lack the 4 O-linked glycosylation sites that correspond to amino acid positions T218, T224, T229, and T237 of native (unprocessed) IL-2Rα (i.e., at least four fewer glycosylations; as evidenced by UniProt; see alignments above; white arrows indicate sites of O-linked glycosylation in the full pre-processed protein that are missing in the truncated protein).
Additionally, Struthers teaches that IL-2 is a potent T cell growth factor that promotes immune responses and is approved by the FDA for use in patients with melanoma and renal cell carcinoma; but that response rates were low in these and other cancers and the therapy was accompanied by sever toxicity (p.1, [0005). Struthers teaches that low-dose IL-2 has been used to selectively boost tolerance to suppress unwanted immune responses associated with autoimmune-like attack of self-tissues; and, selectively promoted key activities of Tregs but not T effector cells and that treatment of mice with low levels of IL-2 prevented autoimmunity (p.1, [0006]. Struthers teaches that low-dose IL-2 therapy is safe but has important drawbacks including a short half-life in vivo, which limits its efficacy, and toxicity at high doses (p.1, [0006]). Struthers teaches IL-2/IL-2Rα fusion proteins that have one or more of the following properties/activities: 1) increasing activity of regulatory T cells (Tregs) and/or increasing immune tolerance in low dose IL-2 based therapies; 2) increasing immune response and memory in higher dose therapies; 3) increasing IL-2 availability when compared to recombinant IL-2; and/or 4) increasing persistent IL-2 stimulation of IL-2R bearing lymphocytes in vivo (p.32, [0282]). Struthers also teaches that truncated versions of IL-2/CD25 (i.e., IL-2/IL-2Rα) have improved stability against aggregation (p.57, [0477]; Example 3).
Struthers teaches that administration of the fusion protein can be used to treat subjects where modulation of the immune response is desirable, for treatment of cancer, and in subjects bearing a virus (i.e., infection; p.27, [0371], [0377]). Struthers teaches that the fusion proteins can be administered for treatment of patients with inflammatory or autoimmune diseases, chronic graft versus host disease, transplant rejection reactions, and other conditions where the goal is to suppress self-reactivity (p.48, [0386]; p.51, section 7.7.2.2). Struthers further teaches that treatment wherein the inflammatory or autoimmune disease is type 1 diabetes, multiple sclerosis, rheumatoid arthritis, celiac disease, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, juvenile idiopathic arthritis, Crohn’s disease, ulcerative colitis or systemic sclerosis, psoriasis, alopecia areata, HCV-induced vasculitis, Sjogren’s syndrome, pemphigus, ankylosing spondylitis, Bechet’s Disease, Wegener’s Granulomatosis, Takayasu’s Disease, autoimmune hepatitis, sclerosing cholangitis, Gougerot-Sjogren, and macrophage activation syndrome (p.51, [0412] and section 7.7.2.2).
Struthers teaches that the fusion protein can be administered via a topical, epidermal, mucosal, intranasal, oral, vaginal, rectal, sublingual, intravenous, intraperitoneal, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intrascapsular, intraorbital, intracardiac, intradermal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, or intrasternal route (p.48, [0384]). Struthers teaches treatment with IL-2/IL-2Rα fusion protein wherein administration occurs every third day on day 0, 3, and 6 (i.e., at least about one day, at least about two days, or at least about 3 days dosing interval; i.e., the dosing interval is the same throughout the doses; p.61, [0486]).
Struthers also teaches that the fusion protein can be co-administered with a second agent that can include one or more therapeutic agents that may be cytotoxic agents, radiotoxic agents, or immunosuppressive agents; anti-neoplastic agents; small molecule drugs, antibodies or antigen binding protein thereof; immune checkpoint inhibitors or stimulators; alkylating agents; antimetabolites; chemotherapies; hormones and steroids, including prednisolone (p.52, [0423] – 56, [0464]; section 7.7.2.5). Struthers teaches that the secondary hormone or steroid agent can be administered prior to or in conjunction with the fusion protein (p.55, [0460]); and, administered concurrently or sequentially (p.55, [0461]); and, that the secondary agent can be administered as desired (p.55, [0460]).
Regarding dosages, Struthers teaches single dose subcutaneous administration of 0.075 mg/kg fusion protein to cynomolgus monkeys (p.4, [0049]; Fig.5; Table 14); and, teaches that the average body weight for the monkeys is 7.8 kg (p.58, [0480]). This would result in administration of approximately 0.585 mg to the subject (i.e., a dose from about 0.1 mg to about 9 mg; i.e., between about 0.3 mg to about 9 mg; i.e., between about 0.1 mg to about 3 mg; i.e., between about 0.1 mg to about 1 mg; i.e., between about 0.3 mg to about 6 mg; i.e., about 5 mg; i.e., about 6 mg). Struthers also discusses both weight-based and flat dosages for human patients. Struthers provides an example weight-based dosage of 3 mg/kg IL-2/IL-2Rα fusion protein for a patient body weight range of 60 kg to 100 kg, which would result in 180 mg to 300 mg (i.e., a dose greater than about 9 mg; p.12, [0128]); and, provides an example of a flat dose of 480 mg of IL-2/IL-2Rα fusion protein (i.e., a dose greater than about 9 mg; p.12, [0129]).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to combine the teachings of App’056 with the teachings of Struthers by using the IL-2/IL-2Rα fusion protein taught by App’056 for the method of increasing Treg activity using the dosages, routes of administration, and dosing intervals taught by Struthers, in order to arrive at the instantly claimed invention, because the combination of teachings by App’056 and Struthers according to known methods results in predictable results. One of ordinary skill in the art would have a reasonable expectation of success because the amino acid sequence identities for the IL-2Rα proteins of App’056 and Struthers both lack the four O-linked glycosylation sites. Further, it would have been obvious to use the fusion protein of App’056 in a method of treating a disease or disorder (including infectious diseases and immune-mediated disorders) and increasing Treg activity because Struthers teaches that the fusion protein can be used for various inflammatory, immune-related, and infectious diseases. One would further be motivated to do so because Struthers teaches that truncated IL-2/IL-2Rα lacking glycosylations provide for enhanced stability.
The combination of App’056 and Struthers does not specifically teach that the subjects treated (i.e., monkeys or mice) with the IL-2/IL-2Rα with modified glycosylation have a stated disease or disorder (instant claim 1); or, wherein one of the two or more doses is administered intravenously and at least one of the two or more doses is administered subcutaneously (instant claim 28).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of App’056 with the additional teachings of Struthers by using the fusion protein comprising an IL-2 polypeptide with at least one fewer glycosylation and an IL-2Rα ECD with at least one, two, three, four, five, six, seven, eight, or nine fewer glycosylations wherein the dose is from about 0.1 mg to about 9 mg or greater than about 9 mg (as taught by Struthers) to treat in a method of treating a disease or disorder such as an inflammatory disease, autoimmune disease, infectious disease, or cancer (taught by App’056 and Struthers), to arrive at the instantly claimed invention, because the combination of teachings by App’056 and Struthers’ suggests that the IL-2/IL-2Rα fusion protein can be used in a method of treatment for the aforementioned diseases. One would also be motivated to do so because Struthers teaches that the fusion protein with truncated IL-2Rα with fewer glycosylations affords greater protein stability and increased Treg activation.
Regarding instant claims 4-5, 14, and 20, the combination of App’056 and Struthers’ teachings does not explicitly teach the following dosages: between about 3 mg to about 9 mg, between about 6 mg to about 9 mg, between about 0.1 mg to about 0.3 mg, or between about 1 mg to about 3 mg (instant claim 4); about 0.1 mg, about 0.3 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 7 mg, about 8 mg, or about 9 mg (instant claim 5); between about 1 mg to about 8 mg, between about 3 mg to about 8 mg, between about 6 mg to about 8 mg, between about 1 mg to about 6 mg, between about 1 mg to about 3 mg, or between about 3 mg to about 6 mg (instant claim 14); or, about 0.1 mg, about 0.3mg,_about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, or about 8 mg (instant claim 20). However, the dosage ranges for administration of the fusion protein to ‘a subject’ taught by Struthers ranges from 0.585 mg (for monkey) to 480 mg (for human). Thus, the dosage ranges of 0.1 mg to 9 mg and doses of greater than 9 mg overlaps substantially with what the prior art teaches.
Thus, it would have also been prima facie obvious for one of ordinary skill in the art before the effective filing date to use the dosages taught and to use routine optimization to arrive at the dosages of instant claims 4-5, 14, and 20 that are not explicitly taught by the combination of App’056 and Struthers. Further, Struthers teaches that weight-based dosages for treatment, which would obviously require adjustments in dosages that may vary slightly from those explicitly taught by Struthers. See MPEP 2144.05.
Regarding instant claim 28, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the combination of teachings of App’056 and Struthers to include both a subcutaneous dose and an intravenous dose (taught by Struthers) for routes of administration for at least two or more of the dose, to arrive at the instantly claimed invention, because Struthers also teaches that subjects were treated on days 0, 3, and 6 and the combination of prior art routes of administration results in a predictable result of treating a disease or disorder in the subject. One of ordinary skill in the art would have a reasonable expectation of success because Struthers teaches that subjects can be treated via various routes of administration and specifically teaches that intravenous and subcutaneous routes of administration were used in (murine) subjects.
The combination of teachings by App’056 and Struthers teaches the method of treating infectious disease or immune-related disease by administration of an IL-2/IL-2Rα fusion protein wherein the IL-2 and IL-2Rα have fewer glycosylations relative to the native proteins, wherein the dose is from about 0.1 mg to about 9 mg, and wherein two or more of the dose are administered at a dosing interval between two doses is at least about one, two, or three days, as described in detail above for instant claims 1, 22, and 31. The combination of App’056 and Struthers also teaches that the fusion protein can be administered with a secondary agent that can be a steroid, including prednisolone that can be administered as desired prior to, in conjunction, concurrently, or sequentially with the fusion protein, as described in detail above.
The combination of teachings by App’056 and Struthers does not teach a dosing interval that is about three weeks (instant claim 25); or, that the steroid treatment is specifically a corticosteroid treatment (instant claim 36).
Boyman teaches low-dose IL-2 for treatment of systemic lupus erythematosus (SLE) and that SLE is an autoimmune disease characterized by a numerical and functional deficit of regulatory T cells (Tregs). Boyman teaches that Tregs are highly dependent of IL-2 and that low doses of IL-2 leads to markedly increased numbers and improved functionality of Treg cells in mice and humans (p.1, para.1). Boyman also teaches subcutaneous injection of IL-2 once daily in 5-day courses with dosing every three weeks for a total of four cycles (p.4, Arms and Interventions table). Boyman teaches that the primary outcome of the study is an increase in percentage of Tregs (p.4, Primary Outcome Measures table) and a secondary outcome of measuring soluble CD25 (IL-2Rα in serum of SLE patients (p.4, Secondary Outcome Measures table). Additionally, Boyman teaches corticosteroid treatment given at a stable dose for at least 4 weeks prior to treatment (p.3, para.1).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of App’056 and Struthers with the teachings of Boyman by treating subjects having a disease or disorder such as SLE with an IL-2/IL-2Rα fusion protein with modified glycosylation (as taught by App’056 and Struthers) by treating patients with a dosing interval of about three weeks (as taught by Boyman), to arrive at the instantly claimed invention, because the combination of prior art elements according to known methods results in a predictable result of treating SLE by increasing activation of Tregs. One of ordinary skill in the art would have a reasonable expectation of success because both Struthers and Boyman teach treatments comprising subcutaneous IL-2-comprising protein administration for activation of Tregs for the treatment of SLE. One of ordinary skill in the art would also have a reasonable expectation of success because Struthers teaches that a disadvantage of low-dose IL-2 is short half-life, but that the IL-2/IL-2Rα fusion protein that has modified glycosylation provides for improved protein stability. Thus, one would be motivated to improve a method of treatment wherein the dosage interval is every three weeks by using a more stable IL-2/IL-2Rα construct for Treg activation. It would also have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of App’056 and Struthers with the teachings of Boyman by using a corticosteroid (taught by Boyman) steroid (taught by Struthers and Boyman) as a second agent (taught by Struthers) in the treatment method by administering the corticosteroid (taught by Boyman) prior to administrating the IL-2/IL-2Rα fusion protein (taught by Struthers). One of ordinary skill in the art would have a reasonable expectation of success because both Struthers and Boyman teach treatment with IL-2-containing proteins in combination with steroids in methods of treating SLE.
The combination of teachings by App’056, Struthers, and Boyman does not teach that the steroid/prednisolone is specifically a corticosteroid (instant claim 36); or that the corticosteroid is administeredorally (instant claim 38).
FDA teaches prescribing information for prednisolone (i.e. Orapred ODT) and teaches that prednisolone is a corticosteroid indicated as an anti-inflammatory or immunosuppressive agent used for treatment of various conditions including allergic conditions, dermatologic diseases, endocrine conditions, gastrointestinal disease, hematologic disease, neoplastic conditions, nervous system conditions, ophthalmic conditions, conditions related to organ transplantation, pulmonary disease, renal conditions, rheumatologic conditions including SLE, and infectious disease (p.1, Indications and Usage; p.3-4). FDA provides dosage information for oral use and warnings and precautions (p.4). FDA further teaches clinical pharmacology for prednisolone with inhibits inflammatory processes (p.10, section 12.1).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of App’056, Struthers, and Boyman with the teachings of FDA by using oral prednisolone corticosteroid (taught by FDA) as the steroid administered prior to, sequentially or concurrently with the IL-2/IL-2Rα fusion protein (as taught by App’056 and Struthers), to arrive at the instantly claimed invention, because the combination of prior art elements according to known methods results in a predictable result. One of ordinary skill would have a reasonable expectation of success because Struthers teaches that a steroid such as prednisolone can be the secondary agent administered and FDA teaches that oral prednisolone is a corticosteroid. Further, one would be motivated to use oral prednisolone because FDA teaches that oral prednisolone tablets can be used to inhibit inflammatory processes and for treatment of patients with autoimmune disease such as SLE.
This is a provisional nonstatutory double patenting rejection.
Patent US11359000B2
Claims 1-5, 13-14, 20, 22, 25-26, 28, 31, 33, 36, 38, 41, 43, and 47-48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. US11359000B2 (herein referred to as Pat’000); and, in further view of Struthers, Boyman, and FDA.
Pat’000 teaches a fusion protein of SEQ ID NO: 16, which aligns 100% with the instant fusion protein comprised of IL-2 SEQ ID NO: 2 and IL-2Rα SEQ ID NO: 3 (Pat’000 claims 1-6; instant claims 1, 41, 43, and 47-48); wherein the fusion protein is deglycosylated (Pat’000 claim 1-6; instant claims 1, 41, 43, and 47-48; see alignment below). Thus, Pat’000 teaches the fusion protein comprising a first polypeptide of IL-2 having at least one fewer glycosylations than native IL-2 and a second polypeptide of IL-2Rα having at least one fewer glycosylations than native IL-2Rα (Pat’000 claim 1; instant claims 1, 47, and 48); wherein the IL-2 shares identity with SEQ ID NO: 2 (Pat’000 claim 4; instant claims 1, 41, 43, 47, and 48, and instant SEQ ID NO: 2); wherein the IL-2Rα shares identity with SEQ ID NO: 12 (Pat’000 claims 4 and 11; instant claims 1, 41, 43, 47, and 48, and instant SEQ ID NOs 1 and 3).
Pat’000 does not teach a method of treating a disease or disorder wherein the fusion protein dose is about 0.1 mg to about 9 mg (instant claims 1) or greater than about 9 mg (instant claim 47), wherein the disorder is an inflammatory, autoimmune (i.e., immune-related), or infectious disease/disorder (instant claims 31 and 33); a method of fusion protein administration for increasing Treg activity wherein the dose is [AltContent: textbox (Instant SEQ ID NO: 2/3 vs. Pat’000 SEQ ID NO: 16
[img-media_image5.png])]from about 0.1 mg to about 9 mg (instant claim 48); routes of administration (instant claim 2); intravenous administration (instant claim 3); subcutaneous administration (instant claim 13); dosages for administration (instant claims 4-5, 14, and 20); dosing intervals of at least about one, two, or three days between two or more of a dose (instant claim 22); a dosing interval of about three weeks (instant claim 25); a method wherein at least one dose is administered intravenously and at least one dose is administered subcutaneously (instant claim 28); a method further comprising administration of a corticosteroid (instant claim 36); or, corticosteroid administration that is oral and that is given prior to (i.e., before), sequentially, or concurrently with administration of the fusion protein (instant claim 38).
Struthers teaches IL-2/IL-2Rα fusion proteins and methods of use thereof (title; abstract; p.4, [0040]); and, wherein IL-2 or IL-2Rα extracellular domain comprises at least one fewer glycosylations, two fewer glycosylations, three fewer glycosylations, four fewer glycosylations, five fewer glycosylations, six fewer glycosylations, seven fewer glycosylations, eight fewer glycosylations, or at least nine fewer glycosylations compared to native IL-2Rα encoded by Struthers’ SEQ ID NO: 7, which aligns 100% with instant SEQ ID NO: 1 (title; abstract; p.1, [0007]; see alignment above for mature IL-2Rα ECD – i.e., no signal sequence).
Struthers additionally teaches an IL-2 polypeptide that has at least one fewer glycosylation compared to native IL-2 of SEQ ID NO: 2, which aligns 100% with instant SEQ ID NO: 2 (p.1, [0007]; see alignment above).
Further, Struthers teaches fusion proteins wherein the IL-2Rα extracellular domain is encoded by SEQ ID NO: 12 (i.e., amino acids 22-202 of pre-processed IL-2Rα), which overlaps with truncated instant amino acid SEQ ID NO: 3 at 100% identity (i.e., amino acids 1-191 of mature IL-2Rα); thus, Struthers’ SEQ ID NO: 12 and the instant SEQ ID NO: 3 both lack the 4 O-linked glycosylation sites that correspond to amino acid positions T218, T224, T229, and T237 of native (unprocessed) IL-2Rα (i.e., at least four fewer glycosylations; as evidenced by UniProt; see alignments above; white arrows indicate sites of O-linked glycosylation in the full pre-processed protein that are missing in the truncated protein).
Additionally, Struthers teaches that IL-2 is a potent T cell growth factor that promotes immune responses and is approved by the FDA for use in patients with melanoma and renal cell carcinoma; but that response rates were low in these and other cancers and the therapy was accompanied by sever toxicity (p.1, [0005). Struthers teaches that low-dose IL-2 has been used to selectively boost tolerance to suppress unwanted immune responses associated with autoimmune-like attack of self-tissues; and, selectively promoted key activities of Tregs but not T effector cells and that treatment of mice with low levels of IL-2 prevented autoimmunity (p.1, [0006]. Struthers teaches that low-dose IL-2 therapy is safe but has important drawbacks including a short half-life in vivo, which limits its efficacy, and toxicity at high doses (p.1, [0006]). Struthers teaches IL-2/IL-2Rα fusion proteins that have one or more of the following properties/activities: 1) increasing activity of regulatory T cells (Tregs) and/or increasing immune tolerance in low dose IL-2 based therapies; 2) increasing immune response and memory in higher dose therapies; 3) increasing IL-2 availability when compared to recombinant IL-2; and/or 4) increasing persistent IL-2 stimulation of IL-2R bearing lymphocytes in vivo (p.32, [0282]). Struthers also teaches that truncated versions of IL-2/CD25 (i.e., IL-2/IL-2Rα) have improved stability against aggregation (p.57, [0477]; Example 3).
Struthers teaches that administration of the fusion protein can be used to treat subjects where modulation of the immune response is desirable, for treatment of cancer, and in subjects bearing a virus (i.e., infection; p.27, [0371], [0377]). Struthers teaches that the fusion proteins can be administered for treatment of patients with inflammatory or autoimmune diseases, chronic graft versus host disease, transplant rejection reactions, and other conditions where the goal is to suppress self-reactivity (p.48, [0386]; p.51, section 7.7.2.2). Struthers further teaches that treatment wherein the inflammatory or autoimmune disease is type 1 diabetes, multiple sclerosis, rheumatoid arthritis, celiac disease, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, juvenile idiopathic arthritis, Crohn’s disease, ulcerative colitis or systemic sclerosis, psoriasis, alopecia areata, HCV-induced vasculitis, Sjogren’s syndrome, pemphigus, ankylosing spondylitis, Bechet’s Disease, Wegener’s Granulomatosis, Takayasu’s Disease, autoimmune hepatitis, sclerosing cholangitis, Gougerot-Sjogren, and macrophage activation syndrome (p.51, [0412] and section 7.7.2.2).
Struthers teaches that the fusion protein can be administered via a topical, epidermal, mucosal, intranasal, oral, vaginal, rectal, sublingual, intravenous, intraperitoneal, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intrascapsular, intraorbital, intracardiac, intradermal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, or intrasternal route (p.48, [0384]). Struthers teaches treatment with IL-2/IL-2Rα fusion protein wherein administration occurs every third day on day 0, 3, and 6 (i.e., at least about one day, at least about two days, or at least about 3 days dosing interval; i.e., the dosing interval is the same throughout the doses; p.61, [0486]).
Struthers also teaches that the fusion protein can be co-administered with a second agent that can include one or more therapeutic agents that may be cytotoxic agents, radiotoxic agents, or immunosuppressive agents; anti-neoplastic agents; small molecule drugs, antibodies or antigen binding protein thereof; immune checkpoint inhibitors or stimulators; alkylating agents; antimetabolites; chemotherapies; hormones and steroids, including prednisolone (p.52, [0423] – 56, [0464]; section 7.7.2.5). Struthers teaches that the secondary hormone or steroid agent can be administered prior to or in conjunction with the fusion protein (p.55, [0460]); and, administered concurrently or sequentially (p.55, [0461]); and, that the secondary agent can be administered as desired (p.55, [0460]).
Regarding dosages, Struthers teaches single dose subcutaneous administration of 0.075 mg/kg fusion protein to cynomolgus monkeys (p.4, [0049]; Fig.5; Table 14); and, teaches that the average body weight for the monkeys is 7.8 kg (p.58, [0480]). This would result in administration of approximately 0.585 mg to the subject (i.e., a dose from about 0.1 mg to about 9 mg; i.e., between about 0.3 mg to about 9 mg; i.e., between about 0.1 mg to about 3 mg; i.e., between about 0.1 mg to about 1 mg; i.e., between about 0.3 mg to about 6 mg; i.e., about 5 mg; i.e., about 6 mg). Struthers also discusses both weight-based and flat dosages for human patients. Struthers provides an example weight-based dosage of 3 mg/kg IL-2/IL-2Rα fusion protein for a patient body weight range of 60 kg to 100 kg, which would result in 180 mg to 300 mg (i.e., a dose greater than about 9 mg; p.12, [0128]); and, provides an example of a flat dose of 480 mg of IL-2/IL-2Rα fusion protein (i.e., a dose greater than about 9 mg; p.12, [0129]).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to combine the teachings of Pat’000 with the teachings of Struthers by using the IL-2/IL-2Rα fusion protein taught by Pat’000 for the method of increasing Treg activity using the dosages, routes of administration, and dosing intervals taught by Struthers, in order to arrive at the instantly claimed invention, because the combination of teachings by Pat’000 and Struthers according to known methods results in predictable results. One of ordinary skill in the art would have a reasonable expectation of success because the amino acid sequence identities for the IL-2 and IL-2Rα proteins of Pat’000 and Struthers are 100% identical. Further, treating a disease or disorder (including infectious diseases and immune-mediated disorders) and increasing Treg activity describe inherent properties of the known fusion protein that do not render the claim patentably new (see MPEP 2112). The instant fusion protein necessarily possesses the same properties as the fusion protein taught by both Pat’000 and Struthers. Thus, the combination of teachings provided by Pat’000 and Struthers teaches instant claims 1, 31, 33, and 47-48 based on inherent structure/function properties.
The combination of Pat’000 and Struthers does not specifically teach that the subjects treated (i.e., monkeys or mice) with the IL-2/IL-2Rα with modified glycosylation have a stated disease or disorder (instant claim 1); or, wherein one of the two or more doses is administered intravenously and at least one of the two or more doses is administered subcutaneously (instant claim 28).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Pat’000 with the additional teachings of Struthers by using the fusion protein comprising an IL-2 polypeptide with at least one fewer glycosylation and an IL-2Rα ECD with at least one, two, three, four, five, six, seven, eight, or nine fewer glycosylations wherein the dose is from about 0.1 mg to about 9 mg or greater than about 9 mg (as taught by Struthers) to treat in a method of treating a disease or disorder such as an inflammatory disease, autoimmune disease, infectious disease, or cancer (taught by Pat’000 and Struthers), to arrive at the instantly claimed invention, because the combination of teachings by Pat’000 and Struthers’ suggests that the IL-2/IL-2Rα fusion protein can be used in a method of treatment for the aforementioned diseases. One would also be motivated to do so because Struthers teaches that the fusion protein with truncated IL-2Rα with fewer glycosylations affords greater protein stability and increased Treg activation.
Regarding instant claims 4-5, 14, and 20, the combination of Pat’000 and Struthers’ teachings does not explicitly teach the following dosages: between about 3 mg to about 9 mg, between about 6 mg to about 9 mg, between about 0.1 mg to about 0.3 mg, or between about 1 mg to about 3 mg (instant claim 4); about 0.1 mg, about 0.3 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 7 mg, about 8 mg, or about 9 mg (instant claim 5); between about 1 mg to about 8 mg, between about 3 mg to about 8 mg, between about 6 mg to about 8 mg, between about 1 mg to about 6 mg, between about 1 mg to about 3 mg, or between about 3 mg to about 6 mg (instant claim 14); or, about 0.1 mg, about 0.3mg,_about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, or about 8 mg (instant claim 20). However, the dosage ranges for administration of the fusion protein to ‘a subject’ taught by Struthers ranges from 0.585 mg (for monkey) to 480 mg (for human). Thus, the dosage ranges of 0.1 mg to 9 mg and doses of greater than 9 mg overlaps substantially with what the prior art teaches.
Thus, it would have also been prima facie obvious for one of ordinary skill in the art before the effective filing date to use the dosages taught and to use routine optimization to arrive at the dosages of instant claims 4-5, 14, and 20 that are not explicitly taught by the combination of Pat’000 and Struthers. Further, Struthers teaches that weight-based dosages for treatment, which would obviously require adjustments in dosages that may vary slightly from those explicitly taught by Struthers. See MPEP 2144.05.
Regarding instant claim 28, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the combination of teachings of Pat’000 and Struthers to include both a subcutaneous dose and an intravenous dose (taught by Struthers) for routes of administration for at least two or more of the dose, to arrive at the instantly claimed invention, because Struthers also teaches that subjects were treated on days 0, 3, and 6 and the combination of prior art routes of administration results in a predictable result of treating a disease or disorder in the subject. One of ordinary skill in the art would have a reasonable expectation of success because Struthers teaches that subjects can be treated via various routes of administration and specifically teaches that intravenous and subcutaneous routes of administration were used in (murine) subjects.
The combination of teachings by Pat’000 and Struthers teaches the method of treating infectious disease or immune-related disease by administration of an IL-2/IL-2Rα fusion protein wherein the IL-2 and IL-2Rα have fewer glycosylations relative to the native proteins, wherein the dose is from about 0.1 mg to about 9 mg, and wherein two or more of the dose are administered at a dosing interval between two doses is at least about one, two, or three days, as described in detail above for instant claims 1, 22, and 31. The combination of Pat’000 and Struthers also teaches that the fusion protein can be administered with a secondary agent that can be a steroid, including prednisolone that can be administered as desired prior to, in conjunction, concurrently, or sequentially with the fusion protein, as described in detail above.
The combination of teachings by Pat’000 and Struthers does not teach a dosing interval that is about three weeks (instant claim 25); or, that the steroid treatment is specifically a corticosteroid treatment (instant claim 36).
Boyman teaches low-dose IL-2 for treatment of systemic lupus erythematosus (SLE) and that SLE is an autoimmune disease characterized by a numerical and functional deficit of regulatory T cells (Tregs). Boyman teaches that Tregs are highly dependent of IL-2 and that low doses of IL-2 leads to markedly increased numbers and improved functionality of Treg cells in mice and humans (p.1, para.1). Boyman also teaches subcutaneous injection of IL-2 once daily in 5-day courses with dosing every three weeks for a total of four cycles (p.4, Arms and Interventions table). Boyman teaches that the primary outcome of the study is an increase in percentage of Tregs (p.4, Primary Outcome Measures table) and a secondary outcome of measuring soluble CD25 (IL-2Rα in serum of SLE patients (p.4, Secondary Outcome Measures table). Additionally, Boyman teaches corticosteroid treatment given at a stable dose for at least 4 weeks prior to treatment (p.3, para.1).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of Pat’000 and Struthers with the teachings of Boyman by treating subjects having a disease or disorder such as SLE with an IL-2/IL-2Rα fusion protein with modified glycosylation (as taught by Pat’000 and Struthers) by treating patients with a dosing interval of about three weeks (as taught by Boyman), to arrive at the instantly claimed invention, because the combination of prior art elements according to known methods results in a predictable result of treating SLE by increasing activation of Tregs. One of ordinary skill in the art would have a reasonable expectation of success because both Struthers and Boyman teach treatments comprising subcutaneous IL-2-comprising protein administration for activation of Tregs for the treatment of SLE. One of ordinary skill in the art would also have a reasonable expectation of success because Struthers teaches that a disadvantage of low-dose IL-2 is short half-life, but that the IL-2/IL-2Rα fusion protein that has modified glycosylation provides for improved protein stability. Thus, one would be motivated to improve a method of treatment wherein the dosage interval is every three weeks by using a more stable IL-2/IL-2Rα construct for Treg activation. It would also have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Pat’000 and Struthers with the teachings of Boyman by using a corticosteroid (taught by Boyman) steroid (taught by Struthers and Boyman) as a second agent (taught by Struthers) in the treatment method by administering the corticosteroid (taught by Boyman) prior to administrating the IL-2/IL-2Rα fusion protein (taught by Struthers). One of ordinary skill in the art would have a reasonable expectation of success because both Struthers and Boyman teach treatment with IL-2-containing proteins in combination with steroids in methods of treating SLE.
The combination of teachings by Pat’000, Struthers, and Boyman does not teach that the steroid/prednisolone is specifically a corticosteroid (instant claim 36); or that the corticosteroid is administered orally (instant claim 38).
FDA teaches prescribing information for prednisolone (i.e. Orapred ODT) and teaches that prednisolone is a corticosteroid indicated as an anti-inflammatory or immunosuppressive agent used for treatment of various conditions including allergic conditions, dermatologic diseases, endocrine conditions, gastrointestinal disease, hematologic disease, neoplastic conditions, nervous system conditions, ophthalmic conditions, conditions related to organ transplantation, pulmonary disease, renal conditions, rheumatologic conditions including SLE, and infectious disease (p.1, Indications and Usage; p.3-4). FDA provides dosage information for oral use and warnings and precautions (p.4). FDA further teaches clinical pharmacology for prednisolone with inhibits inflammatory processes (p.10, section 12.1).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of Pat’000, Struthers, and Boyman with the teachings of FDA by using oral prednisolone corticosteroid (taught by FDA) as the steroid administered prior to, sequentially or concurrently with the IL-2/IL-2Rα fusion protein (as taught by Pat’000 and Struthers), to arrive at the instantly claimed invention, because the combination of prior art elements according to known methods results in a predictable result. One of ordinary skill would have a reasonable expectation of success because Struthers teaches that a steroid such as prednisolone can be the secondary agent administered and FDA teaches that oral prednisolone is a corticosteroid. Further, one would be motivated to use oral prednisolone because FDA teaches that oral prednisolone tablets can be used to inhibit inflammatory processes and for treatment of patients with autoimmune disease such as SLE.
Patent US10787494B2
Claims 1-5, 13-14, 20, 22, 25-26, 28, 31, 33, 36, 38, 41, 43, and 47-48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. US10787494B2 (herein referred to as Pat’484); and, in further view of Struthers, Boyman, and FDA.
Pat’494 teaches a fusion protein of SEQ ID NO: 16, which aligns 100% with the instant fusion protein comprised of IL-2 SEQ ID NO: 2 and IL-2Rα SEQ ID NO: 3 (Pat’484 claim 1; instant claims 1, 41, 43, and 47-48); wherein the fusion protein is deglycosylated (Pat’484 claim 2; instant claims 1, 41, 43, and 47-48; see alignment below). Thus, Pat’494 teaches the fusion protein comprising a first polypeptide of IL-2 having at least one fewer glycosylations than native IL-2 and a second polypeptide of IL-2Rα having at least one fewer glycosylations than native IL-2Rα (Pat’494 claim 1; instant claims 1, 47, and 48); wherein the IL-2 shares identity with SEQ ID NO: 2 (Pat’494 claim 4; instant claims 1, 41, 43, 47, and 48, and instant SEQ ID NO: 2); wherein the IL-2Rα shares identity with SEQ ID NO: 12 (Pat’494 claims 4 and 11; instant claims 1, 41, 43, 47, and 48, and instant SEQ ID NOs 1 and 3).
Pat’494 does not teach a method of treating a disease or disorder wherein the fusion protein dose is about 0.1 mg to about 9 mg (instant claims 1) or greater than about 9 mg (instant claim 47), wherein the disorder is an inflammatory, autoimmune (i.e., immune-related), or infectious disease/disorder (instant claims 31 and 33); a method of fusion protein administration for increasing Treg activity wherein the dose is from about 0.1 mg to about 9 mg (instant claim 48); routes of administration (instant claim 2); intravenous administration (instant claim 3); subcutaneous administration (instant claim 13); dosages for administration (instant claims 4-5, 14, and 20); dosing intervals of at least about one, two, or three days between two or more of a dose (instant claim 22); a dosing interval of about three weeks (instant claim 25); a method [AltContent: textbox (Instant SEQ ID NO: 2/3 vs. Pat’494 SEQ ID NO: 16
[img-media_image5.png])]wherein at least one dose is administered intravenously and at least one dose is administered subcutaneously (instant claim 28); a method further comprising administration of a corticosteroid (instant claim 36); or, corticosteroid administration that is oral and that is given prior to (i.e., before), sequentially, or concurrently with administration of the fusion protein (instant claim 38).
Struthers teaches IL-2/IL-2Rα fusion proteins and methods of use thereof (title; abstract; p.4, [0040]); and, wherein IL-2 or IL-2Rα extracellular domain comprises at least one fewer glycosylations, two fewer glycosylations, three fewer glycosylations, four fewer glycosylations, five fewer glycosylations, six fewer glycosylations, seven fewer glycosylations, eight fewer glycosylations, or at least nine fewer glycosylations compared to native IL-2Rα encoded by Struthers’ SEQ ID NO: 7, which aligns 100% with instant SEQ ID NO: 1 (title; abstract; p.1, [0007]; see alignment above for mature IL-2Rα ECD – i.e., no signal sequence).
Struthers additionally teaches an IL-2 polypeptide that has at least one fewer glycosylation compared to native IL-2 of SEQ ID NO: 2, which aligns 100% with instant SEQ ID NO: 2 (p.1, [0007]; see alignment above).
Further, Struthers teaches fusion proteins wherein the IL-2Rα extracellular domain is encoded by SEQ ID NO: 12 (i.e., amino acids 22-202 of pre-processed IL-2Rα), which overlaps with truncated instant amino acid SEQ ID NO: 3 at 100% identity (i.e., amino acids 1-191 of mature IL-2Rα); thus, Struthers’ SEQ ID NO: 12 and the instant SEQ ID NO: 3 both lack the 4 O-linked glycosylation sites that correspond to amino acid positions T218, T224, T229, and T237 of native (unprocessed) IL-2Rα (i.e., at least four fewer glycosylations; as evidenced by UniProt; see alignments above; white arrows indicate sites of O-linked glycosylation in the full pre-processed protein that are missing in the truncated protein).
Additionally, Struthers teaches that IL-2 is a potent T cell growth factor that promotes immune responses and is approved by the FDA for use in patients with melanoma and renal cell carcinoma; but that response rates were low in these and other cancers and the therapy was accompanied by sever toxicity (p.1, [0005). Struthers teaches that low-dose IL-2 has been used to selectively boost tolerance to suppress unwanted immune responses associated with autoimmune-like attack of self-tissues; and, selectively promoted key activities of Tregs but not T effector cells and that treatment of mice with low levels of IL-2 prevented autoimmunity (p.1, [0006]. Struthers teaches that low-dose IL-2 therapy is safe but has important drawbacks including a short half-life in vivo, which limits its efficacy, and toxicity at high doses (p.1, [0006]). Struthers teaches IL-2/IL-2Rα fusion proteins that have one or more of the following properties/activities: 1) increasing activity of regulatory T cells (Tregs) and/or increasing immune tolerance in low dose IL-2 based therapies; 2) increasing immune response and memory in higher dose therapies; 3) increasing IL-2 availability when compared to recombinant IL-2; and/or 4) increasing persistent IL-2 stimulation of IL-2R bearing lymphocytes in vivo (p.32, [0282]). Struthers also teaches that truncated versions of IL-2/CD25 (i.e., IL-2/IL-2Rα) have improved stability against aggregation (p.57, [0477]; Example 3).
Struthers teaches that administration of the fusion protein can be used to treat subjects where modulation of the immune response is desirable, for treatment of cancer, and in subjects bearing a virus (i.e., infection; p.27, [0371], [0377]). Struthers teaches that the fusion proteins can be administered for treatment of patients with inflammatory or autoimmune diseases, chronic graft versus host disease, transplant rejection reactions, and other conditions where the goal is to suppress self-reactivity (p.48, [0386]; p.51, section 7.7.2.2). Struthers further teaches that treatment wherein the inflammatory or autoimmune disease is type 1 diabetes, multiple sclerosis, rheumatoid arthritis, celiac disease, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, juvenile idiopathic arthritis, Crohn’s disease, ulcerative colitis or systemic sclerosis, psoriasis, alopecia areata, HCV-induced vasculitis, Sjogren’s syndrome, pemphigus, ankylosing spondylitis, Bechet’s Disease, Wegener’s Granulomatosis, Takayasu’s Disease, autoimmune hepatitis, sclerosing cholangitis, Gougerot-Sjogren, and macrophage activation syndrome (p.51, [0412] and section 7.7.2.2).
Struthers teaches that the fusion protein can be administered via a topical, epidermal, mucosal, intranasal, oral, vaginal, rectal, sublingual, intravenous, intraperitoneal, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intrascapsular, intraorbital, intracardiac, intradermal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, or intrasternal route (p.48, [0384]). Struthers teaches treatment with IL-2/IL-2Rα fusion protein wherein administration occurs every third day on day 0, 3, and 6 (i.e., at least about one day, at least about two days, or at least about 3 days dosing interval; i.e., the dosing interval is the same throughout the doses; p.61, [0486]).
Struthers also teaches that the fusion protein can be co-administered with a second agent that can include one or more therapeutic agents that may be cytotoxic agents, radiotoxic agents, or immunosuppressive agents; anti-neoplastic agents; small molecule drugs, antibodies or antigen binding protein thereof; immune checkpoint inhibitors or stimulators; alkylating agents; antimetabolites; chemotherapies; hormones and steroids, including prednisolone (p.52, [0423] – 56, [0464]; section 7.7.2.5). Struthers teaches that the secondary hormone or steroid agent can be administered prior to or in conjunction with the fusion protein (p.55, [0460]); and, administered concurrently or sequentially (p.55, [0461]); and, that the secondary agent can be administered as desired (p.55, [0460]).
Regarding dosages, Struthers teaches single dose subcutaneous administration of 0.075 mg/kg fusion protein to cynomolgus monkeys (p.4, [0049]; Fig.5; Table 14); and, teaches that the average body weight for the monkeys is 7.8 kg (p.58, [0480]). This would result in administration of approximately 0.585 mg to the subject (i.e., a dose from about 0.1 mg to about 9 mg; i.e., between about 0.3 mg to about 9 mg; i.e., between about 0.1 mg to about 3 mg; i.e., between about 0.1 mg to about 1 mg; i.e., between about 0.3 mg to about 6 mg; i.e., about 5 mg; i.e., about 6 mg). Struthers also discusses both weight-based and flat dosages for human patients. Struthers provides an example weight-based dosage of 3 mg/kg IL-2/IL-2Rα fusion protein for a patient body weight range of 60 kg to 100 kg, which would result in 180 mg to 300 mg (i.e., a dose greater than about 9 mg; p.12, [0128]); and, provides an example of a flat dose of 480 mg of IL-2/IL-2Rα fusion protein (i.e., a dose greater than about 9 mg; p.12, [0129]).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to combine the teachings of Pat’494 with the teachings of Struthers by using the IL-2/IL-2Rα fusion protein taught by Pat’494 for the method of increasing Treg activity using the dosages, routes of administration, and dosing intervals taught by Struthers, in order to arrive at the instantly claimed invention, because the combination of teachings by Pat’494 and Struthers according to known methods results in predictable results. One of ordinary skill in the art would have a reasonable expectation of success because the amino acid sequence identities for the IL-2 and IL-2Rα proteins of Pat’494 and Struthers are 100% identical. Further, treating a disease or disorder (including infectious diseases and immune-mediated disorders) and increasing Treg activity describe inherent properties of the known fusion protein that do not render the claim patentably new (see MPEP 2112). The instant fusion protein necessarily possesses the same properties as the fusion protein taught by both Pat’494 and Struthers. Thus, the combination of teachings provided by Pat’494 and Struthers teaches instant claims 1, 31, 33, and 47-48 based on inherent structure/function properties.
The combination of Pat’494 and Struthers does not specifically teach that the subjects treated (i.e., monkeys or mice) with the IL-2/IL-2Rα with modified glycosylation have a stated disease or disorder (instant claim 1); or, wherein one of the two or more doses is administered intravenously and at least one of the two or more doses is administered subcutaneously (instant claim 28).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Pat’494 with the additional teachings of Struthers by using the fusion protein comprising an IL-2 polypeptide with at least one fewer glycosylation and an IL-2Rα ECD with at least one, two, three, four, five, six, seven, eight, or nine fewer glycosylations wherein the dose is from about 0.1 mg to about 9 mg or greater than about 9 mg (as taught by Struthers) to treat in a method of treating a disease or disorder such as an inflammatory disease, autoimmune disease, infectious disease, or cancer (taught by Pat’494 and Struthers), to arrive at the instantly claimed invention, because the combination of teachings by Pat’494 and Struthers’ suggests that the IL-2/IL-2Rα fusion protein can be used in a method of treatment for the aforementioned diseases. One would also be motivated to do so because Struthers teaches that the fusion protein with truncated IL-2Rα with fewer glycosylations affords greater protein stability and increased Treg activation.
Regarding instant claims 4-5, 14, and 20, the combination of Pat’494 and Struthers’ teachings does not explicitly teach the following dosages: between about 3 mg to about 9 mg, between about 6 mg to about 9 mg, between about 0.1 mg to about 0.3 mg, or between about 1 mg to about 3 mg (instant claim 4); about 0.1 mg, about 0.3 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 7 mg, about 8 mg, or about 9 mg (instant claim 5); between about 1 mg to about 8 mg, between about 3 mg to about 8 mg, between about 6 mg to about 8 mg, between about 1 mg to about 6 mg, between about 1 mg to about 3 mg, or between about 3 mg to about 6 mg (instant claim 14); or, about 0.1 mg, about 0.3mg,_about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, or about 8 mg (instant claim 20). However, the dosage ranges for administration of the fusion protein to ‘a subject’ taught by Struthers ranges from 0.585 mg (for monkey) to 480 mg (for human). Thus, the dosage ranges of 0.1 mg to 9 mg and doses of greater than 9 mg overlaps substantially with what the prior art teaches.
Thus, it would have also been prima facie obvious for one of ordinary skill in the art before the effective filing date to use the dosages taught and to use routine optimization to arrive at the dosages of instant claims 4-5, 14, and 20 that are not explicitly taught by the combination of Pat’494 and Struthers. Further, Struthers teaches that weight-based dosages for treatment, which would obviously require adjustments in dosages that may vary slightly from those explicitly taught by Struthers. See MPEP 2144.05.
Regarding instant claim 28, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the combination of teachings of Pat’494 and Struthers to include both a subcutaneous dose and an intravenous dose (taught by Struthers) for routes of administration for at least two or more of the dose, to arrive at the instantly claimed invention, because Struthers also teaches that subjects were treated on days 0, 3, and 6 and the combination of prior art routes of administration results in a predictable result of treating a disease or disorder in the subject. One of ordinary skill in the art would have a reasonable expectation of success because Struthers teaches that subjects can be treated via various routes of administration and specifically teaches that intravenous and subcutaneous routes of administration were used in (murine) subjects.
The combination of teachings by Pat’494 and Struthers teaches the method of treating infectious disease or immune-related disease by administration of an IL-2/IL-2Rα fusion protein wherein the IL-2 and IL-2Rα have fewer glycosylations relative to the native proteins, wherein the dose is from about 0.1 mg to about 9 mg, and wherein two or more of the dose are administered at a dosing interval between two doses is at least about one, two, or three days, as described in detail above for instant claims 1, 22, and 31. The combination of Pat’494 and Struthers also teaches that the fusion protein can be administered with a secondary agent that can be a steroid, including prednisolone that can be administered as desired prior to, in conjunction, concurrently, or sequentially with the fusion protein, as described in detail above.
The combination of teachings by Pat’494 and Struthers does not teach a dosing interval that is about three weeks (instant claim 25); or, that the steroid treatment is specifically a corticosteroid treatment (instant claim 36).
Boyman teaches low-dose IL-2 for treatment of systemic lupus erythematosus (SLE) and that SLE is an autoimmune disease characterized by a numerical and functional deficit of regulatory T cells (Tregs). Boyman teaches that Tregs are highly dependent of IL-2 and that low doses of IL-2 leads to markedly increased numbers and improved functionality of Treg cells in mice and humans (p.1, para.1). Boyman also teaches subcutaneous injection of IL-2 once daily in 5-day courses with dosing every three weeks for a total of four cycles (p.4, Arms and Interventions table). Boyman teaches that the primary outcome of the study is an increase in percentage of Tregs (p.4, Primary Outcome Measures table) and a secondary outcome of measuring soluble CD25 (IL-2Rα in serum of SLE patients (p.4, Secondary Outcome Measures table). Additionally, Boyman teaches corticosteroid treatment given at a stable dose for at least 4 weeks prior to treatment (p.3, para.1).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of Pat’494 and Struthers with the teachings of Boyman by treating subjects having a disease or disorder such as SLE with an IL-2/IL-2Rα fusion protein with modified glycosylation (as taught by Pat’494 and Struthers) by treating patients with a dosing interval of about three weeks (as taught by Boyman), to arrive at the instantly claimed invention, because the combination of prior art elements according to known methods results in a predictable result of treating SLE by increasing activation of Tregs. One of ordinary skill in the art would have a reasonable expectation of success because both Struthers and Boyman teach treatments comprising subcutaneous IL-2-comprising protein administration for activation of Tregs for the treatment of SLE. One of ordinary skill in the art would also have a reasonable expectation of success because Struthers teaches that a disadvantage of low-dose IL-2 is short half-life, but that the IL-2/IL-2Rα fusion protein that has modified glycosylation provides for improved protein stability. Thus, one would be motivated to improve a method of treatment wherein the dosage interval is every three weeks by using a more stable IL-2/IL-2Rα construct for Treg activation. It would also have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Pat’494 and Struthers with the teachings of Boyman by using a corticosteroid (taught by Boyman) steroid (taught by Struthers and Boyman) as a second agent (taught by Struthers) in the treatment method by administering the corticosteroid (taught by Boyman) prior to administrating the IL-2/IL-2Rα fusion protein (taught by Struthers). One of ordinary skill in the art would have a reasonable expectation of success because both Struthers and Boyman teach treatment with IL-2-containing proteins in combination with steroids in methods of treating SLE.
The combination of teachings by Pat’494, Struthers, and Boyman does not teach that the steroid/prednisolone is specifically a corticosteroid (instant claim 36); or that the corticosteroid is administered orally (instant claim 38).
FDA teaches prescribing information for prednisolone (i.e. Orapred ODT) and teaches that prednisolone is a corticosteroid indicated as an anti-inflammatory or immunosuppressive agent used for treatment of various conditions including allergic conditions, dermatologic diseases, endocrine conditions, gastrointestinal disease, hematologic disease, neoplastic conditions, nervous system conditions, ophthalmic conditions, conditions related to organ transplantation, pulmonary disease, renal conditions, rheumatologic conditions including SLE, and infectious disease (p.1, Indications and Usage; p.3-4). FDA provides dosage information for oral use and warnings and precautions (p.4). FDA further teaches clinical pharmacology for prednisolone with inhibits inflammatory processes (p.10, section 12.1).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to further combine the teachings of Pat’494, Struthers, and Boyman with the teachings of FDA by using oral prednisolone corticosteroid (taught by FDA) as the steroid administered prior to, sequentially or concurrently with the IL-2/IL-2Rα fusion protein (as taught by Pat’494 and Struthers), to arrive at the instantly claimed invention, because the combination of prior art elements according to known methods results in a predictable result. One of ordinary skill would have a reasonable expectation of success because Struthers teaches that a steroid such as prednisolone can be the secondary agent administered and FDA teaches that oral prednisolone is a corticosteroid. Further, one would be motivated to use oral prednisolone because FDA teaches that oral prednisolone tablets can be used to inhibit inflammatory processes and for treatment of patients with autoimmune disease such as SLE.
Conclusion
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/JAMI MICHELLE GURLEY/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647