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 .
DETAILED ACTION
Status of Application, Amendments, And/Or Claims
Applicant’s amendment of the specification filed 12 April 2023 has been entered. Applicant’s amendment of the claims filed 10 February 2026 has been entered.
Election/Restrictions
In the response received on 10 February 2026, Applicant elected, without traverse, the invention of Group I, claims 1-97, wherein the modified IL-2 polypeptide comprises a substitution with a natural or unnatural amino acid at the position of Y31. Applicant further elected the species of:
A-a) wherein the modified IL-2 polypeptide comprising an amino acid sequence having at least 80% identity to SEQ ID NO: 1;
B-a) wherein the modified IL-2 polypeptide is conjugated to a water-soluble polymer;
D-a) wherein the modified IL-2 polypeptide is conjugated to a water-soluble polymer, a lipid, a protein, or a peptide via a single amino acid residue, and wherein the single amino acid residue is located within the modified IL-2 polypeptide;
E) wherein the water-soluble polymer is polyethylene glycol (PEG);
F-a) wherein the water-soluble polymer comprising a linear PEG molecule; and
G-a) wherein the modified IL-2 polypeptide is conjugated to a water-soluble polymer, a lipid, a protein, or a peptide through a linker.
Claims 3, 6-15, 17-37, 40-41, 44, 46, 48-49, 51-57, 59, 61-67, 71-89, 91-97, 99-115 and 117-124 are cancelled. Claims 1-2, 4-5, 16, 38-39, 42-43, 45, 47, 50, 58, 60, 68-70, 90, 98 and 116 are pending. Claims 98 and 116 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1-2, 4-5, 16, 38-39, 42-43, 45, 47, 50, 58, 60, 68-70 and 90 are under examination to the extent they read on the elected species. Claims 1-2, 4, 16, 38-39, 42-43, 45, 47, 50, 58, 60, 68-70 and 90 read on the elected species, and claim 5 is withdrawn as being drawn to nonelected species.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claim 1 is objected to because of the following informalities:
In claim 1, the part “h) combinations of a) through g)” should be deleted because the combination is already included by using the term “and/or” in each of a) through g). Further, the listing of a) through h) has typographical errors (e.g., two “b” and no “c”).
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-2, 4, 39, 42-43, 45, 47, 58, 60 and 90 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wittrup et al. (U.S. Patent No. 7,569,215 B2, Date of Patent: Aug. 4, 2009).
Wittrup teaches mutant IL-2 polypeptides that have increased affinity for binding to IL-2Ra, as compared to the wild-type IL-2 (SEQ ID NO: 2) or PROLEUKIN (SEQ ID NO: 3) (col. 2, lines 22-29). Wittrup teaches that the mutant IL-2 polypeptides have an amino acid sequence that differs from the wild-type IL-2 (SEQ ID NO: 2) by one or more amin acid substitutions, e.g., at 2, 3, 4, …10, 11 or more positions (col. 2, lines 29-34, lines 38-46); for example, a mutant of IL-2 (SEQ ID NO: 2) with the mutations of (p) N30S, Y31C, T37A, V69A, A73V, Q74P, H79R, and I128T (col. 3, lines 15-32). Wittrup teaches that the mutant IL-2 polypeptides can also be prepared as fusion or chimeric polypeptides, e.g., with an Fc region of an antibody (col. 13, lines 1-16). The mutant IL-2 polypeptides taught by Wittrup meet the requirement of “having at least 80% identity to SEQ ID NO: 1 or SEQ ID NO: 2” of instant claim 1 (SEQ ID NO: 1 differs from the wild-type human IL-2 (SEQ ID NO: 3) by the substitution of C125S; and SEQ ID NO: 2 differs from the wild-type human IL-2 by the substitution of A1M). Wittrup further teaches using recombinant expression to produce the mutant IL-2 polypeptides (col. 15, lines 17-23)
Therefore, Wittrup anticipates the instant claims.
Claims 1-2, 39, 42-43, 45, 47, 50, 58, 60, 68-70 and 90 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Greve (U.S. Patent No. 10,035,836 B1, Date of Patent: Jul. 31, 2018).
Greve teaches variants of IL-2 with single amino acid substitutions at specific positions in the IL-2 sequence that enable stable and specific chemical conjugation of PEG molecules to the specific amino acid positions (“PEG conjugation sites”) while retaining the ability of the IL-2-PEG conjugate to bind to and activate the IL2Rabg receptor, and consequently activate Treg cells (col. 4, lines 5-17). Greve teaches that the IL-2 moieties for site-specific PEG conjugation are engineered to have free (unpaired) cysteine residues because of the very specific reactivity of thiols with malemide- and iodoacetimide-activated PEG reagents; and the constructs are made on the background of wild-type human IL-2 with the substitution C125S to remove the only unpaired cysteine residue in IL-2, and the substitution N88R, which reduces affinity for IL2Rb and thus selective for IL2Rabg (IL-2 selective agonist activity) (col. 8, lines 35-61). Greve teaches that an Fc fusion protein with the variants of IL-2 will have similar the activity (col. 11, lines 13-38). Greve teaches that the amino acid residues that can be used for conjugating PEG to IL-2 include, e.g., D109 and E100 (col. 16, lines 4-19). Greve further teaches that the variants of IL-2 may include conservative substitutions, including Y31F (col. 12, lines 27-29). The variants of IL-2 taught by Greve meet the requirement of “having at least 80% identity to SEQ ID NO: 1 or SEQ ID NO: 2” of instant claim 1 (SEQ ID NO: 1 differs from the wild-type human IL-2 (SEQ ID NO: 3) by the substitution of C125S; and SEQ ID NO: 2 differs from the wild-type human IL-2 by the substitution of A1M). Greve teaches recombinant expression to prepare the variant IL-2 proteins of the invention and the fusion molecules thereof (col. 8, line 63 through col. 9, line 7). Greve further teaches pharmaceutical compositions comprising the IL-2-PEG conjugates or fusion proteins thereof (col. 13, lines 11-18; col. 14, lines 50-60).
Therefore, Greve anticipates the instant claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 16 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Wittrup et al. (U.S. Patent No. 7,569,215 B2), as applied to 1-2, 4, 39, 42-43, 45, 47, 58, 60 and 90 above, and further in view of Bernett et al (US 2019/0241638 A1, Pub Date: Aug. 8, 2019).
Wittrup teaches as set forth above. Wittrup, however, does not teach wherein the mutant IL-2 polypeptide comprises substitutions of L18M and L19S (claims 16, 38).
Bernett teaches that IL-2 suffers from a very fast clearance due in part to internalization of the IL-2:IL-2R complex, and that an IL-2 variant (2D1) which has L18M/L19S mutations has demonstrated a longer half-life than the wild-type IL-2 as the IL-2 variant has a higher affinity for IL-2Ra at endosomal pH than the wild-type IL-2 does [0254].
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include amino acid substitutions of L18M/L19S in the mutant IL-2 polypeptides of Wittrup. One of ordinary skill in the art would have been motivated to do so, because Wittrup teaches generating mutant IL-2 polypeptides that have increased affinity for binding to IL-2Ra than the wild-type IL-2 by introducing one or more amin acid substitutions in the IL-2 sequence, and Bernett further teaches that including L18M/L19S mutations in the wild-type IL-2 sequence can increase the affinity for binding to IL-2Ra and the half-life of the IL-2. Therefore, the combined teachings provide a reasonable expectation of success in making mutant IL-2 polypeptides with improved properties.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Greve (U.S. Patent No. 10,035,836 B1), as applied to 1-2, 39, 42-43, 45, 47, 50, 58, 60, 68-70 and 90 above, and further in view of Bernett et al (US 2019/0241638 A1, Pub Date: Aug. 8, 2019).
Greve teaches as set forth above. Greve, however, does not teach wherein the variants of IL-2 comprise substitutions at positions of L18 and L19 (claim 16).
Bernett teaches that IL-2 suffers from a very fast clearance due in part to internalization of the IL-2:IL-2R complex, and that an IL-2 variant (2D1) which has L18M/L19S mutations has demonstrated a longer half-life than the wild-type IL-2 as the IL-2 variant has a higher affinity for IL-2Ra at endosomal pH than the wild-type IL-2 does [0254].
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include amino acid substitutions of L18M/L19S in the variants of IL-2 taught by Greve. One of ordinary skill in the art would have been motivated to do so, because Greve teaches generating variants of IL-2 that selectively bind to and activate the IL2Rabg receptor by introducing amino acid substitutions in the wild-type IL-2 sequence, and Bernett further teaches that including L18M/L19S mutations in the wild-type IL-2 sequence can increase the affinity for binding to IL-2Ra and the half-life of the IL-2. Therefore, the combined teachings provide a reasonable expectation of success in making variants of IL-2 with improved properties.
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.
Claims 1-2, 4, 39, 42-43, 45, 47, 50, 58, 60, 68-70 and 90 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 35-36, 49, 53, 58, 72, 78, 82, 101 and 112-115 of copending Application No. 17/634,022 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other. Independent claim 1 of the ‘022 application recites “A modified IL-2 polypeptide conjugate comprising a modified interleukin 2 (IL-2) polypeptide, which modified interleukin 2 (IL-2) polypeptide comprises an amino acid sequence set forth in SEQ ID NO:1 or SEQ ID NO:2 and a substitution with cysteine at a position of Y31, and is conjugated to a water-soluble polymer, a lipid, or a polypeptide through a linker; and/or via a single amino acid residue in a fusion polypeptide that comprises said modified IL-2 polypeptide and an additional amino acid sequence.” The essential features of the instant claims are present in the claims of the ‘022 application. Regarding claims 50 and 58, Greve (U.S. Patent No. 10,035,836 B1) (cited above) teaches conjugating a PEG molecule at a position with a substituted amino acid (see above 102 section). Therefore, the claims of the ‘022 application anticipate and render obvious of the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
NO CLAIM IS ALLOWED.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Xiaozhen Xie, whose telephone number is 571-272-5569. The examiner can normally be reached on M-F, 8:30-5.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa L. Ford, can be reached on 571-272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
/XIAOZHEN XIE/Primary Examiner, Art Unit 1674