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 a 35 U.S.C. 371 national phase application and claims priority to International Application No. PCT/KR2021/005487 (filing date 04/29/2021), which claims the benefit of the prior-filed Korean Provisional Patent Application Nos. KR10-2020-0052913 (filing date 04/29/2020) and KR10-2020-0052513 (filing date 04/29/2020).
Status of Application/Claims
The amendment, filed 012/09/2026, is acknowledged. Claims 8 and 19 are canceled. No claims are currently amended. Claims 1-7, 9-18, and 20-21 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/09/2026 has been fully considered by the examiner.
Withdrawn Objections & Rejections
Regarding the Specification objection for trade names and/or trademark compliance issues, applicant amendment has addressed the issue. Thus, the objection is withdrawn.
Regarding the rejection for claim 19 under 35 U.S.C. 101 for non-statutory subject matter: Applicant amendment has addressed the rejections for claim 19. Claim 19 has been canceled; thus, the rejection for claim 19 is withdrawn.
Regarding the rejection for claim 19 under 35 U.S.C. 112(b) for indefiniteness: Applicant amendment has addressed the rejections for claim 19. Claim 19 has been canceled; thus, the rejection for claim 19 is withdrawn.
Regarding the rejection for claim 8 under 35 U.S.C. 112(a) for enablement: Applicant amendment has addressed the rejection for claim 8. Claim 8 has been canceled; thus, the rejection for claim 8 is withdrawn.
Claim Objections
(New Objection)
The status of every claim in such listing must be indicated after its claim number by one of the following identifiers in a parenthetical expression: (Original), (Currently Amended), (Canceled), (Withdrawn), (Previously Presented), (New), and (Not Entered). See MPEP 1893.01(a)(4).
Claim 21 does not have a status indicator.
Claim Rejections - 35 USC § 103
(Maintained Rejections)
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, 7, 9-18, and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Shin, et al. WO2016163764A2 (herein referred to as Shin), and further in view of Runkel, et al. Structural and functional differences between glycosylated forms of human interferon-β (IFN-β). Pharmaceutical Research (1998), 15:4, p.641-649 (herein referred to as Runkel).
Shin teaches pharmaceutical preparations that comprise a human IFN-β variant comprising an amino acid sequence having an R27T substitution for the purpose of improving and treating multiple sclerosis, cancer, autoimmune disease, viral infections, HIV infectious diseases, and hepatitis C (p.1, abstract; instant claims 1, 7-8, and 19-21). Amino acid sequence alignment shows 100% identity between Shin’s IFN-β and instant SEQ ID NO: 2 (see sequence alignment below; instant claims 1 and 10):
[AltContent: textbox (Sequence alignment: Instant SEQ ID NO: 2 vs. Shin IFN-β
[img-media_image1.png])]
Shin teaches that IFN-β is a spherical protein of 22 kD and is comprised of 5 alpha-helical domains with sugar chains of 18 kD. Shin further teaches a method for improving stability of IFN-β that is imparted by the R27T substitution because the substitution results in additional glycosylation at position 25 (p.2, para.5; instant claim 9). Shin teaches that one of the major challenges in the development of protein pharmaceuticals is to provide products with a long shelf life of more than 24 months by giving them sufficient chemical, physical, and biological stability (p.2, para.6). Shin teaches that challenges are due to various factors such as protein aggregation, physicochemical instability, low half-life, low solubility and pharmacokinetic properties (p.2, para.7).
Shin does not teach that the IFN-β variant comprises a C17S substitution (instant claim 1 and 9).
[AltContent: textbox (Sequence alignment: Instant SEQ ID NO: 3 vs. Shin IFN-β
[img-media_image2.png])]The only difference between Shin’s IFN-β and instant SEQ ID NO: 3 is the C17S mutation (see sequence alignment below):
Runkel teaches glycosylated IFN-β (i.e., IFN-β-1a) and unglycosylated IFN-β (i.e., IFN-β-1b) proteins and that the glycosylation of IFN-β contributes to activity and reduced thermal denaturation sensitivity; whereas, unglycosylated forms produced more aggregates and reduced anti-viral activity (abstract). Runkel also teaches the addition of the C17S mutation which results in increased yield of biologically active IFN-β (p.1, col.2, para.1). Runkel also teaches that human IFN-β has three cysteine residues that can form disulfide bonds, and that denaturation, and thus aggregation, in the C17S mutant may be reduced because disulfide scrambling is likely reduced in the mutant (p.8, col.1, para.2).
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 combine the teachings of Shin and Runkel by modifying the R27T mutant that has increased glycosylation (as taught by Shin) to have an additional C17S mutation (as taught by Runkel) to arrive at the instantly claimed invention, in order to receive the added expected benefit (as taught by Runkel) that the C17S substitution results in less denaturation and aggregation of the protein. One of ordinary skill in the art would have a reasonable expectation of success because Shin and Runkel teach that the R27T and C17S mutations, respectively, contribute to enhanced stability, which would predictably result in higher yield of the IFN-βprotein.
Regarding claim 21: As the resulting IFN-β differs from WT IFN-β only by the R27T and C17S mutations, the resulting protein exhibits 98.2% identity to WT IFN-β (i.e., at least 90% homology to SEQ ID NO: 1; see sequence alignment below; instant claim 21).
[AltContent: textbox (Sequence alignment: WT IFN-β/SEQ ID NO:1 vs. R27T/C17S Double Mutant IFN-β
[img-media_image3.png])]
Regarding claims 11-18: Shin and Runkel do not explicitly teach that the method for improving stability, recited in claim 9, is purification stability, storage stability, or freeze/thawing stability (instant claim 11); that the purification stability improves purification efficiency of 2 glycosylation proteins (instant claim 12); that the purification stability reduces the protein aggregation during concentration and buffer exchange (instant claim 13); that the storage stability is storage stability in a buffer of pH 2.0 to 6.0 (instant claim 14); that the buffer is acetic acid or sodium phosphate (instant claim 15); that the freeze/thawing stability is thawing stability after freezing at -100 ºC to -10 ºC (instant claim 16); that the freeze/thawing stability is freeze/thawing stability in an acetic acid buffer (instant claim 17); or, that the freeze/thawing stability reduces the protein aggregation and degradation after 3 times or more freeze/thawing cycles (instant claim 18). These limitations further describe the method of improving stability recited in claim 9, which are solely due to the structural properties are IFN-β double mutant and which is identical to the IFN-β protein taught by Shin and Runkel.
There no indication that anything other than the inherent structure of the IFN-β double mutant, which is recited in the prior art (as taught by Shin and Runkel), is responsible for the properties recited in claims 11-18. Further, as evidenced by the specification, the disclosure recites:
“In addition, the present inventors have conducted intensive research to develop a method for improving stability of an R27T variant, which was a human interferon-beta variant, more specifically, purification stability, storage stability, and freeze/thawing stability, found that it was possible to achieve the object by substituting serine for the 17th amino acid cysteine, which was the 17th amino acid of the R27T variant, and then completed the present invention.” (p.7, para.10).
Accordingly, the claims are rendered obvious by the prior art.
Claims 2-6 are rejected under 35 U.S.C. 103 as being unpatentable over Shin and Runkel as applied to claim 1and further in view of Song, et al. Glycoengineering of interferon-β 1a improves its biophysical and pharmacokinetic properties. PLOS ONE (2014), 9:5, p.1-14 (herein referred to as Song).
The combined teachings of Shin and Runkel as applied to claim 1 were as discussed above.
Shin and Runkel do not teach a polynucleotide encoding a IFN-β variant (instant claim 2); wherein the variant comprises SEQ ID NO: 3, which encodes for the R27T/C17S double variant (instant claim 3); an expression vector comprising the polynucleotide (instant claim 4); that an animal cell is transformed with the expression vector (instant claim 5); or, a method for preparing a the IFN-β variant comprising culturing of the animal cell (instant claim 6).
Song teaches the same R27T IFN-β construct as Shin, which would have the same structural properties. Song further teaches the reduced propensity for aggregation and increased half-life due to the R27T mutation (abstract). Song further teaches cloning, expression, and growth (i.e., culturing) of vectors carrying the gene (i.e., polynucleotide) encoding the R27T variant in CHO cells (i.e., animal cells) (p.2, col.1, para.5; instant claims 2-6).
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 combine the teachings of Shin and Runkel with Song by modifying the R27T mutant that has increased glycosylation (as taught by Shin) to have an additional C17S mutation (as taught by Runkel) to arrive at the instantly claimed invention, in order to receive the added expected benefit (as taught by Runkel) that the C17S substitution results in less denaturation and aggregation of the protein; and, to express the IFNβ R27T/C17S double mutant (as taught by Shin and Runkel) by culturing animal/CHO cells that are transfected with IFN-β (as taught by Song). One of ordinary skill in the art would have a reasonable expectation of success because Song teaches that IFN-β variants can be expressed using vectors carrying a polynucleotides.
Double Patenting
(Maintained Rejection)
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.
17/922,179
Claims 1-7, 9-18, and 20-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim claims 1, 3, 6, 8, 10-16 of copending Application No. 17/922,179 (herein referred to as App’179). Although the claims at issue are not identical, they are not patentably distinct from each other because App’179 teaches an IFN-β and a method for improving stability of the variant via substituting amino acid residues R27T and C17S to produce a double mutant variant, which is relative to the WT amino acid sequence (App’179 claims 1, 3, and 11-13; instant claims 1, 9-10 and 21). App’179 teaches pharmaceutical compositions comprising the IFN-β R27T/C17S double mutant for the purpose of treating cancer (i.e., its use as an anti-cancer agent; App’179 claims 10 and 15-16; instant claims 7-8 and 19-20). App’179 also teaches culturing the IFN-β variant in host cells that are mammalian cells (i.e., animal cells) using vectors comprising a polynucleotide encoding the variant (App’179 6, 8, 11, and 14; instant claims 2-6).
Regarding claims 11-18: App’179 do not explicitly teach that the method for improving stability, recited in claim 9, is purification stability, storage stability, or freeze/thawing stability (instant claim 11); that the purification stability improves purification efficiency of 2 glycosylation proteins (instant claim 12); that the purification stability reduces the protein aggregation during concentration and buffer exchange (instant claim 13); that the storage stability is storage stability in a buffer of pH 2.0 to 6.0 (instant claim 14); that the buffer is acetic acid or sodium phosphate (instant claim 15); that the freeze/thawing stability is thawing stability after freezing at -100 ºC to -10 ºC (instant claim 16); that the freeze/thawing stability is freeze/thawing stability in an acetic acid buffer (instant claim 17); or, that the freeze/thawing stability reduces the protein aggregation and degradation after 3 times or more freeze/thawing cycles (instant claim 18). These limitations further describe the method of improving stability recited in claim 9, which are solely due to the structural properties are IFN-β double mutant and which is identical to the IFN-β protein taught by Shin and Runkel.
There no indication that anything other than the inherent structure of the IFN-β double mutant, which is recited in the prior art (as taught by Shin and Runkel), is responsible for the properties recited in claims 11-18. Further, as evidenced by the specification, the disclosure recites:
“In addition, the present inventors have conducted intensive research to develop a method for improving stability of an R27T variant, which was a human interferon-beta variant, more specifically, purification stability, storage stability, and freeze/thawing stability, found that it was possible to achieve the object by substituting serine for the 17th amino acid cysteine, which was the 17th amino acid of the R27T variant, and then completed the present invention.” (p.7, para.10).
Accordingly, the claims are anticipated by App’179.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Regarding the rejections for claims 1 and 7-21 and claims 2-6 under 35 U.S.C. 103 for obviousness and the non-statutory double patenting rejections for claims 1-21: Applicant submits remarks, filed 02/09/2026, in which applicant submits unexpected results. While obviousness rejections may sometimes be overcome by submission of unexpected results, applicant arguments are not persuasive as the combination of prior art teachings teaches the IFNβ variant as well as the motivations for the C17S and R27T mutations. Thus, the combination of prior art teaches the claimed variant at 100% identity. As the prior art teaches the claimed variant at 100% structural identity, the claimed variant necessarily possesses the same properties as the variant taught by the combination of prior art teachings described above. Thus, the obviousness and non-statutory double patenting rejections are maintained based on inherent structure/function properties (see MPEP §2112).
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jami M Gurley whose telephone number is (571)272-0117. The examiner can normally be reached Monday - Friday, 8am - 4pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at 571-272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAMI MICHELLE GURLEY/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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