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, filed 02/26/2024 is a 371 filing of PCT/CN2022/106105, filed 07/15/2022, and claims foreign priority to a Chinese application CN202110982310.8, filed 08/25/2021. Certified copy of foreign priority application was filed on 02/26/2024.
Status of Claims/Application
The preliminary amendment of 02/26/2024 is acknowledged. Claims 1-19, filed on 02/26/2024, are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/26/2024, 07/11/2025, and 10/17/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 7 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The invention appears to employ novel biological materials, specifically CHO-K1 cell line (“China General Microbiological Culture Collection Center on May 26, 2022, under CGMCC No. 45173”). Since the biological materials are essential to the claimed invention, they must be obtainable by a repeatable method set forth in the specification or otherwise readily available to the public. If the biological materials are not so obtainable or available, the requirements of 35 U.S.C. 112 may be satisfied by a deposit of the biological materials. The specification does not disclose a repeatable process to obtain the biological materials and it is not apparent if the biological materials are readily available to the public. It is noted that Applicant has deposited the biological materials (page 23 of the Specification), but there is no indication in the specification as to public availability as required by 37 C.F.R. 1.808.
US patent applications comprising a biological deposit in addition to adherence to the Budapest Treaty, must further comply with 37 C.F.R. 1.808 (a) in which a person in position to assert that the deposit was made under conditions that assure that:
(1) Access to the deposit will be available during pendency of the patent application making reference to the deposit to one determined by the Director to be entitled thereto under § 1.14 and 35 U.S.C. 122, and
(2) Subject to paragraph (b) of this section, all restrictions imposed by the depositor on the availability to the public of the deposited material will be irrevocably removed upon the granting of the patent.
An affidavit or declaration by Applicant, or a statement by an attorney of record over his or her signature and registration number, stating that the specific biological materials that have been deposited under the Budapest Treaty and that the biological materials will be irrevocably and without restriction or condition released to the public upon the issuance of a patent, would satisfy the deposit requirement made herein.
Applicant may provide assurance of compliance by an affidavit or declaration, or by a statement by an attorney of record over his or her signature and registration number, showing that:
(a) during the pendency of this application, access to the invention will be afforded to the Commissioner upon request;
(b) all restrictions upon availability to the public will be irrevocably removed upon granting of the patent;
(c) the deposit will be maintained in a public depository for a period of 30 years or 5 years after the last request or for the effective life of the patent, whichever is longer;
(d) a test of the viability of the biological material at the time of the deposit will be made (see 37 C.F.R. 1.807); and
(e) the deposit will be replaced if it should ever become inviable.
Because the condition of 37 CFR 1.808(a) has not been met the claim 7 is rejected under 35 USC 112(a) as failing to provide an enabling disclosure.
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 2, 4, 7, 9, 12, 14, 17, and 19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 2, 4, 7, 9, 12, 14, 17, and 19, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are required of the claimed invention. See MPEP § 2173.05(d). It is suggested the applicant revise the claims to remove the term “preferably” and the limitations following it. For the purposes of compact prosecution, the examiner considers the limitations prior of the phrase “preferably” on the merits herein.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 14 and 19 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The phrase “preferably every 14-18 days; preferably, the fusion protein is administered every 14-28 days, preferably every 14-28 days” in claim 14 and similarly in claim 19 do not limit the claim further than the limitation every 14-28. The phrase renders the claim limitation redundant. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 1-19 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent 10,696,724 B2 (Winston hereinafter, issued 06/30,2020) and further in view of US 2014/0286898 A1 (hereinafter Gavin, published 09/25/2014), Mizui (Mizui M. Natural and modified IL-2 for the treatment of cancer and autoimmune diseases. Clin Immunol. 2019 Sep;206:63-70. doi: 10.1016/j.clim.2018.11.002. Epub 2018 Nov 8. PMID: 30415086) and as evidenced by Website webpath.med.utah.edu (https://web.archive.org/web/20201028171542/https://webpath.med.utah.edu/GIHTML/GI100.html, publicly available on 10/28/2020, accessed 07/24/2024).
Regarding instant claim 1,
Winston teaches fusion proteins that are conditionally active variants of IL-2 (abstract) wherein the IL-2 is fused to human serum albumin to extend serum half-life (col 4, lines 43-46) to use to treat inflammatory diseases (col 2, lines 1-6, “compositions and methods of using the proteins and nucleic acids for the treatment of a disease or disorder, such as proliferative disease, a tumorous disease, an inflammatory disease, an immunological disorder, an autoimmune disease, an infectious disease, a viral disease, an allergic reaction, a parasitic reaction, graft-versus-host disease and the like”).
Winston teaches a fusion protein of interleukin 2, comprising: a human interleukin 2 or its variant; and human serum albumin or its variant, wherein the human interleukin 2 or its variants includes: an amino acid sequence as shown in SEQ ID NO: 1; or, an amino acid sequence having at least 90% sequence identity with the amino acid sequence as shown in SEQ ID NO:1 (col 49, lines 3-13, “The amino acid sequence within mutant IL-2 polypeptides can vary from SEQ ID NO: 1 (UniProtKB accession number P60568) by virtue of containing (or only containing) one or more amino acid substitutions, which may be considered conservative or non-conservative substitutions. Non-naturally occurring amino acids can also be incorporated. Alternatively, or in addition, the amino acid sequence can vary from SEQ ID NO: 1 (which may be considered the “reference” sequence) by virtue of containing and addition and/or deletion of one or more amino acid residues”).
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Figure 1 SEQ ID NO: 1 of Winston has 99.4% identity to SEQ ID NO: 1 of the instant application.
the human serum albumin or its variants includes: an amino acid sequence as shown in SEQ ID NO:2; or, an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:2 (col 27, lines 24-28, “ In one embodiment, the half-life extension element is a human serum albumin (HSA) binding domain. HSA (SEQ ID NO: 2) may also be directly bound to the pharmaceutical compositions or bound via a short linker Fragments of HSA may also be used”, see figure below for alignment of SEQ ID NO:2 of Winston and instant SEQ ID NO:2).
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Figure 2. SEQ ID NO: 2 of Winston has 98.9% identity to SEQ ID NO: 2 of the instant application.
Regarding instant claim 2,
Winston teaches the fusion protein according to claim 1, wherein the fusion protein includes the amino acid sequence as shown in SEQ ID NO:1 and the amino acid sequence as shown in SEQ ID NO:2; preferably, the amino acid at position 125 of the amino acid sequence as shown in SEQ ID NO:1 is not cysteine; preferably, the amino acid at position 125 of the amino acid sequence as shown in SEQ ID NO:1 is replaced with serine or alanine (col 50, lines 15-23, “As noted above, any of the mutant IL-2 polypeptides disclosed herein can include the sequences described; they can also be limited to the sequences described and otherwise identical to SEQ ID NO: 1. Moreover, any of the mutant IL-2 polypeptides described herein can optionally include a substitution of the cysteine residue at position 125 with another residue (e.g., serine) and/or can optionally include a deletion of the alanine residue at position 1 of SEQ ID NO: 1.”).
Regarding instant claim 3,
Winston teaches the human interleukin 2 or its variant is connected to the human serum albumin or its variant directly or via a linking peptide (col 42, lines 56-67, “protease-cleavable linker sequences. The linker sequence serves to provide flexibility between polypeptides, such that each polypeptide is capable of inhibiting the activity of the first polypeptide. The linker sequence can be located between any or all of the cytokine polypeptide, fragment or mutein thereof, the blocking moiety, and serum half-life extension element”).
Regarding instant claim 4,
Winston teaches the linking peptide has a general formula of (GnS)m, in which n or m is an integer selected from 1 to 10, preferably, the linking peptide has a general formula of (GnS)m, in which n is an integer selected from 1 to 4, and m is an integer selected from 0 to 3 (col 42, lines 63-67, “Optionally, the composition comprises, two, three, four, or five linker sequences. The linker sequence, two, three, or four linker sequences can be the same or different linker sequences. In one embodiment, the linker sequence comprises GGGGS (SEQ ID NO: 132)”).
Regarding instant claim 5,
Winston teaches the fusion protein has an amino acid sequence as shown in SEQ ID NO:4 (SEQ ID NO: 101, 99.6% similarity). The difference in the 0.4% is the C125A substitution in the IL-2 protein and the linker sequence GGGGS wherein the linker sequence of the instant application is one GGGGS linker shorter than the sequence from Winston. The difference is obvious to modify the portions to result in the outcome of instant SEQ ID NO: 4 is based on the following suggestions taught by Winston. Winston teaches that the IL-2 polypeptide can optionally include substitution of the cysteine residue at position 125 as described earlier (col 50, lines 15-23) and further teaches that the linker sequence serves to provide flexibility between polypeptides, such that each polypeptide is capable of inhibiting the activity of the first polypeptide and the GGGGS linker can be one, two, three or four linker sequences which can be the same or different linker sequences (col 42, lines 63-67). The C125A substitution beneficial as evidenced by Gavin. Gavin teaches IL-2 muteins and IL-2 mutein Fc-fusion molecules that preferentially expand and activate T regulatory cells and are amenable to large scale production (abstract). Gavin further teaches the C125A mutation improved manufacturing (para 0153, "In these constructs, the C125A mutation was used in place of C1255 for improved manufacturing").
Therefore, it would have been obvious to the person of ordinary skill in the art to modify the SEQ ID NO: 101 as taught by Winston with the C125A substitution to improve manufacturing as taught by Gavin and optimize 1-4 linker GGGGS sequences to provide flexibility between two polypeptides.
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Figure 3. Winston SEQ ID NO: 101 (Db) has 99.6% identity of the SEQ ID NO: 4 (Qy) of the instant application.
Regarding instant claim 6,
Winston teaches the isolated nucleic acid molecule encoding the fusion protein as defined in claim 1 (col 5, lines 36-39, “This disclosure also related to nucleic acids, e.g., DNA, RNA, mRNA, that encode the conditionally active proteins described herein, as well as vectors and host cells that contain such nucleic acids”).
Regarding instant claim 7,
Winston teaches a CHO cell expression system was used to produce the IL-2 fusion proteins (col 53, lines 49-54, “A CHO cell expression system (Flp-In®, Life Technologies), a derivative of CHO-K1 Chinese Hamster ovary cells (ATCC, CCL-61) (Kao and Puck, Proc. Natl. Acad Sci USA 1968; 60(4):1275-81), is used. Adherent cells are subcultured according to standard cell culture protocols provided by Life Technologies”). It is noted that the claim has the limitation “preferably CHO-K1 cell, deposited in China General Microbiological Culture Collection center 05/26/2022, CGMCC No. 45173.” However, as the phrase “preferably” is stated, the claimed invention does not require the specific cell line as Winston teaches that any other CHO-K1 cell line is able to produce the IL-2 fusion protein.
Regarding instant claim 8,
Winston teaches the fusion protein and a pharmaceutically acceptable carrier (col 43, lines 45-47, “Provided herein are pharmaceutical formulations or compositions containing the chimeric polypeptides and a pharmaceutically acceptable carrier”).
Regarding instant claim 9,
Winston teaches a pharmaceutical composition wherein the composition is in a dosage form of injection, tablet or capsule (col 44, lines 24-48, e.g. “preparation for parenteral administration […] “aqueous solution, suspension”, “oral administration include […] capsules, sachets, or tablets”).
Regarding instant claims 10, 11, 12, 13, 14, 15, 16, 18, 17, and 19,
Winston teaches a method for treating and preventing inflammatory bowel disease (IBD), comprising administering to a subject of an effective amount of the fusion protein of claim 1 (claims 10, 11, 12, 13, 14) or pharmaceutical composition of claim 8 (claim 15, 16, 18, 17, 19) (col 42, lines 13-21, “Further provided are methods of treating a subject with or at risk of developing an of a disease or disorder, such as proliferative disease, a tumorous disease, an inflammatory disease, an immunological disorder, an autoimmune disease, an infectious disease, a viral disease, an allergic reaction, a parasitic reaction, or graft-versus-host disease. The methods administering to a subject in need thereof an effective amount of a fusion protein as disclosed herein that is typically administered as a pharmaceutical composition” and col 42, line 53, “inflammatory bowel disease”).
Regarding instant claims 11 and 16,
While Winston does not explicitly state IBD comprises ulcerative colitis, Crohn’s disease and indeterminate colitis, these subtypes are part of the inflammatory bowel disease genus as evidenced by Website webpath.med.utah.edu (https://web.archive.org/web/20201028171542/https://webpath.med.utah.edu/GIHTML/GI100.html, publicly available on 10/28/2020, accessed 07/24/2024). The Website webpath.med.utah.edu discloses that Crohn’s disease and ulcerative colitis are best known forms of IBD (line 2) and that 1/6 idiopathic IBD cases are termed indeterminate colitis because they are not distinguishable between Crohn’s disease or ulcerative colitis. Therefore, Winston’s disclosure of IBD disease encompasses ulcerative colitis, Crohn’s disease and indeterminate colitis.
Regarding instant claims 12 and 17,
Winston teaches the method further comprises administering the fusion protein or the pharmaceutical composition orally or by injection (col 44, lines 12-23, e.g. “orally”, “intravenously”, “subcutaneously”).
Regarding instant claim 13, 18, 14 and 19,
Winston does not teach the fusion protein is administered at 3 X 104 IU to 1 X 106 IU each dose and the fusion protein or pharmaceutical composition is administered every 7-28 days.
Mizui teaches the dosages of natural and modified IL-2 for the treatment of cancer and autoimmune diseases one of which is Crohn’s disease and ulcerative colitis (page 206, Table 2. Ongoing clinical trials showing recombinant protein IL-2 is administered at “1 MIU (million international units – 106 IU) 5 days every 2 weeks”(page 2016, Table 2). Mizui teaches low doses of IL-2 targets the expansion of Tregs and treatment of autoimmune diseases (page 63, column 1 paragraph 1, and page 65 Fig 1).
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Figure 4. Mizui teaches a low-dose IL-2 to induce Treg expansion and treating autoimmune diseases.
Therefore, it would have been obvious to the person of ordinary skill in the art to use dosage ranges that are already in clinical trials taught by Mizui with the IL-2 fusion polypeptide of Winston and expect reasonable success at treating IBD. Furthermore, Winston teaches that dosage optimization is determined by one of skill in the art, like a physician, who determines doses by the side effects, patient population, etc. (col 47, lines 40-64). In regards to the specific dosage and interval amounts recited in the instant claims "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that treatment (ie dosage and intervals) optimization is obvious."
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.
Claim 1-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 2, 3, 4, 5, 8 and 9 of copending Application No. 18/686,504 in view of Winston (cited previously), Mizui (cited previously) and as evidenced by Website webpath.med.utah.edu (cited previously).
Regarding instant claim 1, 2, and 7, App504 claim 1 recites an expression system characterized in that the expression system expresses a fusion protein of human interleukin-2 and human serum albumin, wherein the fusion protein comprises: a human interleukin-2 or a variant thereof, wherein the human interleukin-2 or a variant thereof comprises: an amino acid sequence set forth in SEQ ID NO: 1; an amino acid sequence set forth in SEQ ID NO: 1 having one or more amino acids substitution, deletion and/or addition and meanwhile retaining equivalent functions; or an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1; and a human serum albumin or a variant thereof, wherein the human serum albumin or a variant thereof comprises: an amino acid sequence set forth in SEQ ID NO: 2; an amino acid sequence set forth in SEQ ID NO: 2 having one or more amino acids substitution, deletion and/or addition and meanwhile retaining equivalent functions; or an amino acid sequence having at least 90% sequence identity to the amino acid sequence set forth in SEQ ID NO: 2. App504 claim 2 recites the expression system is a CHO cell preferably a CHO-K1 cells.
Regarding instant claim 1, App504 claim 3 recites the expression system according to claim 1, characterized in that the fusion protein of human interleukin-2 and human serum albumin comprises an amino acid sequence set forth in SEQ ID NO: 1 and an amino acid sequence set forth in SEQ ID NO: 2. SEQ ID NO: 1 of the instant and the App504 have 100% similarity (see alignment below). Likewise, SEQ ID NO: 2 of the instant and the App504 have 100% similarity.
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Regarding instant claim 2, App504 claim 4 recites the expression system according to claim 3, characterized in that the amino acid at position 125 of SEQ ID NO: 1 in the fusion protein is not cysteine; preferably, the amino acid at position 125 is substituted with serine or alanine.
Regarding instant claim 3 and 4, App504 claim 5 recites he expression system according to any one of claims I to 4, characterized in that the human interleukin-2 or a variant thereof is directly connected to the human serum albumin or a variant thereof, or the human interleukin-2 or a variant thereof is connected to the human serum albumin or a variant thereof via a linker peptide, preferably, the linker peptide is represented by a general formula (GnS)in, wherein n and m are an integer from 1 to 10, respectively; more preferably, n is an integer from 1 to 4, and m is an integer from 0 to 3.
Regarding instant claim 5 and 6, App504 claim 8 recites the expression system according to claim 1, characterized in that the fusion protein is encoded by a nucleotide sequence set forth in SEQ ID NO: 3. Instant SEQ ID NO: 4 has 100% match of the nucleotide sequence in App504 SEQ ID NO: 3 when translated to amino acid sequence (see below for the alignment analysis)
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Regarding instant claim 5, App504 claim 9 recites the expression system according to claim 1, characterized in that the fusion protein of human interleukin-2 and human serum albumin has an amino acid sequence set forth in SEQ ID NO: 4. The instant SEQ ID NO: 4 and SEQ ID NO: 4 of App504 are 100% similar.
However, App504 claims do not recite a pharmaceutical composition of the fusion protein and a pharmaceutically acceptable carrier (instant claim 8), the pharmaceutical composition is in dosage form of injection, tablet or capsule (instant claim 9).
Winston teaches fusion proteins that are conditionally active variants of IL-2 (abstract) wherein the IL-2 is fused to human serum albumin to extend serum half-life (col 4, lines 43-46) to use to treat inflammatory diseases (col 2, lines 1-6, “compositions and methods of using the proteins and nucleic acids for the treatment of a disease or disorder, such as proliferative disease, a tumorous disease, an inflammatory disease, an immunological disorder, an autoimmune disease, an infectious disease, a viral disease, an allergic reaction, a parasitic reaction, graft-versus-host disease and the like”).
Winston teaches the fusion protein and a pharmaceutically acceptable carrier (col 43, lines 45-47, “Provided herein are pharmaceutical formulations or compositions containing the chimeric polypeptides and a pharmaceutically acceptable carrier”).
Winston teaches a pharmaceutical composition wherein the composition is in a dosage form of injection, tablet or capsule (col 44, lines 24-48, e.g. “preparation for parenteral administration […] “aqueous solution, suspension”, “oral administration include […] capsules, sachets, or tablets”).
Therefore, it would have been obvious to the person of ordinary skill in the art to use the pharmaceutical compositions of Winston with the IL-2 fusion protein of App504 to formulate a pharmaceutical composition that has a high serum half-life and can be used to treat inflammatory diseases as taught by Winston.
However, App504 claims do not teach the method for treating or preventing inflammatory bowel disease comprising administering to the subject and effective amount of the fusion protein IL-2 or the pharmaceutical composition of IL-2 fusion protein (instant claims 10 and 15), wherein the IBD comprise ulcerative colitis, Crohn’s disease and indeterminate colitis (instant claims 11 and 16), the fusion protein or pharmaceutical composition of the fusion protein is administered orally or by injection (instant claims 12 and 17); the fusion protein is administered at 3 X 104 IU to 1 X 106 IU each dose (instant claims 13 and 18), and is administered every 14-28 days (instant claims 14 and 19).
Winston teaches a method for treating and preventing inflammatory bowel disease (IBD), comprising administering to a subject of an effective amount of the fusion protein of claim 1 (claims 10, 11, 12, 13, 14) or pharmaceutical composition of claim 8 (claim 15, 16, 18, 17, 19) (col 42, lines 13-21, “Further provided are methods of treating a subject with or at risk of developing an of a disease or disorder, such as proliferative disease, a tumorous disease, an inflammatory disease, an immunological disorder, an autoimmune disease, an infectious disease, a viral disease, an allergic reaction, a parasitic reaction, or graft-versus-host disease. The methods administering to a subject in need thereof an effective amount of a fusion protein as disclosed herein that is typically administered as a pharmaceutical composition” and col 42, line 53, “inflammatory bowel disease”).
While Winston does not explicitly state IBD comprises ulcerative colitis, Crohn’s disease and indeterminate colitis, these subtypes are part of the inflammatory bowel disease genus as evidenced by Website webpath.med.utah.edu (https://web.archive.org/web/20201028171542/https://webpath.med.utah.edu/GIHTML/GI100.html, publicly available on 10/28/2020, accessed 07/24/2024). The Website webpath.med.utah.edu discloses that Crohn’s disease and ulcerative colitis are best known forms of IBD (line 2) and that 1/6 idiopathic IBD cases are termed indeterminate colitis because they are not distinguishable between Crohn’s disease or ulcerative colitis. Therefore, Winston’s disclosure of IBD disease encompasses ulcerative colitis, Crohn’s disease and indeterminate colitis.
In another aspect, Winston does not teach the fusion protein is administered at 3 X 104 IU to 1 X 106 IU each dose and the fusion protein or pharmaceutical composition is administered every 7-28 days.
Mizui teaches the dosages of natural and modified IL-2 for the treatment of cancer and autoimmune diseases one of which is Crohn’s disease and ulcerative colitis (page 206, Table 2. Ongoing clinical trials showing recombinant protein IL-2 is administered at “1 MIU (million international units – 106 IU) 5 days every 2 weeks”(page 2016, Table 2). Mizui teaches low doses of IL-2 targets the expansion of Tregs and treatment of autoimmune diseases (page 63, column 1 paragraph 1, and page 65 Fig 1)
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Figure 5. Mizui teaches a low-dose IL-2 to induce Treg expansion and treating autoimmune diseases.
Therefore, it would have been obvious to the person of ordinary skill in the art to use dosage ranges that are already in clinical trials taught by Mizui with the IL-2 fusion polypeptide of App504 and expect reasonable success at treating IBD. Furthermore, Winston teaches that dosage optimization is determined by one of skill in the art, like a physician, who determines doses by the side effects, patient population, etc. (col 47, lines 40-64). In regards to the specific dosage and interval amounts recited in the instant claims "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. Moreover, it is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the dosage regimen of a known drug is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of treatment because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the pharmaceutical art. Therefore, it would be conventional and within the skill of the art to identify the optimal dosages administered and optimal intervals to achieve target levels and therapeutically effective doses. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It is clear that both the prior art and claimed method perform the same protocol to achieve the same results. It would be conventional and within the skill of the art to determine the optimal treatment regimens. Accordingly, one can see that the courts, over a period of over 50 years, have consistently held that treatment (ie dosage and intervals) optimization is obvious."
This is a provisional nonstatutory double patenting rejection.
Claim 1-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1,2,3,4,5,6,7,8,9,11,12,13,16,17, and 18 of copending Application No. 18/686,430, App430 hereinafter, filed 02/25/2024 in view of Winston (cited previously) and as evidenced by Website webpath.med.utah.edu (cited previously)
Regarding instant claim 1, App430 claim 1 recites A fusion protein of interleukin 2, comprising: a human interleukin 2 or its variant; and human serum albumin or its variant, wherein the human interleukin 2 or its variants includes: an amino acid sequence as shown in SEQ ID NO: 1; or, an amino acid sequence having at least 90% sequence identity with the amino acid sequence as shown in SEQ ID NO:1; the human serum albumin or its variants includes: an amino acid sequence as shown in SEQ ID NO:2; or, an amino acid sequence having at least 90% sequence identity with the amino acid sequence shown in SEQ ID NO:2.
Regarding instant claim 2, App430 claim 2 recites the fusion protein includes the amino acid sequence as shown in SEQ ID NO:1 and the amino acid sequence as shown in SEQ ID NO:2; preferably, the amino acid at position 125 of the amino acid sequence as shown in SEQ ID NO:1 is not cysteine; preferably, the amino acid at position 125 of the amino acid sequence as shown in SEQ ID NO:1 is replaced with serine or alanine.
Regarding instant claim 3, App430 claim 3 recites the human interleukin 2 or its variant is connected to the human serum albumin or its variant directly or via a linking peptide.
Regarding instant claim 4, App430 claim 4 recites the linking peptide has a general formula of (GnS)m, in which n or m is an integer selected from 1 to 10; preferably, the linking peptide has a general formula of (GnS)m, in which n is an integer selected from 1 to 4, and m is an integer selected from 0 to 3.
Regarding instant claim 5, App430 claim 5 recites the fusion protein has an amino acid sequence as shown in SEQ ID NO:4.
Regarding instant claim 6, App430 claim 6 recites an isolated nucleic acid molecule encoding the fusion protein as defined in claims 1.
Regarding instant claim 7, App430 claim 7 recites an expression system comprising a CHO cell which contains the nucleic acid molecule as defined in An expression system comprising a CHO cell which contains the nucleic acid molecule, preferably, the expression system is CHO-Kl cell, which is deposited in China General Microbiological Culture Collection Center on May 26, 2022, under CGMCC No. 45173.
Regarding instant claim 8, App430 claim 8 recites a pharmaceutical composition comprising the fusion protein as defined in claim 1 and a pharmaceutically acceptable carrier.
Regarding instant claim 9, App430 claim 9 recite the pharmaceutical composition is in a dosage form of injection, tablet or capsule; preferably, the dosage form is selected from solution for injection or lyophilized powder for injection; preferably, the carrier is selected from excipient, diluent, filler, binder, wetting agent, disintegrant, absorption enhancer, surfactant, absorptive support, and/or stabilizer.
Regarding instant claim 12, App430 claim 11 recite the fusion protein or the pharmaceutical composition is administered orally or by injection, preferably is injected subcutaneously or intravenously.
Regarding instant claim 13, App430 claim 12 recite the fusion protein is administered at 3x104 IU to 1x 106 IU each dose; preferably, the pharmaceutical composition is administered at 3 x 10 4IU to 1 x 106IU each dose, as measured by the fusion protein therein.
Regarding instant claim 14, App430 claim 13 recite the fusion protein is administered every 7-28 days.
Regarding instant claim 17, App430 claim 16 recite the pharmaceutical composition is administered orally or by injection, preferably is injected subcutaneously or intravenously.
Regarding instant claim 18, App430 claim 17 recite pharmaceutical composition is administered at 3 x 10 4IU to 1 x 106 IU each dose, as measured by the fusion protein therein.
Regarding instant claim 19, App430 claim 18 recite the method according to claim 17, the pharmaceutical composition is administered every 7-28 days, preferably every 14-28 days.
While, App430 claims 10, 14, 15, and 19 recite a method of treating or preventing ALS by administering the fusion protein IL-2 and the pharmaceutical composition, App430 claims do not recite a method of treating or preventing inflammatory bowel disease comprising administering to the subject and effective amount of the fusion protein IL-2 or the pharmaceutical composition of IL-2 fusion protein (instant claims 10 and 15), wherein the IBD comprise ulcerative colitis, Crohn’s disease and indeterminate colitis (instant claims 11 and 16).
Winston teaches fusion proteins that are conditionally active variants of IL-2 (abstract) wherein the IL-2 is fused to human serum albumin to extend serum half-life (col 4, lines 43-46) to use to treat inflammatory diseases (col 2, lines 1-6, “compositions and methods of using the proteins and nucleic acids for the treatment of a disease or disorder, such as proliferative disease, a tumorous disease, an inflammatory disease, an immunological disorder, an autoimmune disease, an infectious disease, a viral disease, an allergic reaction, a parasitic reaction, graft-versus-host disease and the like”).
Winston teaches a method for treating and preventing inflammatory bowel disease (IBD), comprising administering to a subject of an effective amount of the fusion protein of claim 1 (claims 10, 11, 12, 13, 14) or pharmaceutical composition of claim 8 (claim 15, 16, 18, 17, 19) (col 42, lines 13-21, “Further provided are methods of treating a subject with or at risk of developing an of a disease or disorder, such as proliferative disease, a tumorous disease, an inflammatory disease, an immunological disorder, an autoimmune disease, an infectious disease, a viral disease, an allergic reaction, a parasitic reaction, or graft-versus-host disease. The methods administering to a subject in need thereof an effective amount of a fusion protein as disclosed herein that is typically administered as a pharmaceutical composition” and col 42, line 53, “inflammatory bowel disease”).
While Winston does not explicitly state IBD comprises ulcerative colitis, Crohn’s disease and indeterminate colitis, these subtypes are part of the inflammatory bowel disease genus as evidenced by Website webpath.med.utah.edu (https://web.archive.org/web/20201028171542/https://webpath.med.utah.edu/GIHTML/GI100.html, publicly available on 10/28/2020, accessed 07/24/2024). The Website webpath.med.utah.edu discloses that Crohn’s disease and ulcerative colitis are best known forms of IBD (line 2) and that 1/6 idiopathic IBD cases are termed indeterminate colitis because they are not distinguishable between Crohn’s disease or ulcerative colitis. Therefore, Winston’s disclosure of IBD disease encompasses ulcerative colitis, Crohn’s disease and indeterminate colitis.
Therefore, it would have been obvious to the person of ordinary skill in the art to use fusion protein IL-2 and the pharmaceutical composition and the method of treating and preventing an inflammatory disease such as ALS as recited by App430 and apply it to IBD as taught by Winston.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/LAM THUY VI TRAN HO/Examiner, Art Unit 1647 /L.T./Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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