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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 2/4/26 has been entered.
Claims 1, 10, 36, 49, 78, 111-115 have been amended. Claims 2-9, 11-34, 37-48, 50-52, 54-57, 59-71, 73-77, 79-81, 84-89, 91-98, 100, and 102-110 have been canceled. Claims 1, 10, 35, 36, 49, 53, 58, 72, 78, 82, 83, 90, 99, 101, and 111-115 are pending.
Claims 35, 82, 83, 90, 99 and 101 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/10/25.
Claims 1, 10, 36, 49, 53, 58, 72, 78, and 111-115 are under examination.
Withdrawn Rejections
The rejection of claim 49 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn in light of Applicant’s amendment thereto. See paragraph 11, page 3 of the previous Office action.
The rejection of claims 1, 36, 78, and 111-115 under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Wittrup et al. (WO 2005007121 A1, published January 27, 2005), is withdrawn in light of Applicant’s amendment thereto. See paragraph 18, page 5 of the previous Office action.
New Rejection Necessitated by Applicant’s Amendment
Claim Rejections - 35 USC § 112
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.
Claims 53 and 72 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.
Claim 53 recites “wherein the additional amino acid sequence comprises an antibody sequence or a fragment thereof”. There is insufficient antecedent basis for this limitation in the claim. Claim 53 depends from claim 49, and there is no recitation of an additional amino acid sequence. Clarification and/or correction is required.
Claim 72 is indefinite because it states that the modified IL-2 is conjugated to a polypeptide; however, claim 49 from which the claim depends limits the fusion partner to a water-soluble polymer. It is unclear if the IL-2 is conjugated to a water soluble polymer or a polypeptide. Clarification and/or correction is required.
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 72 is 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. Although claim 72 depends from a preceding claim, the claim does not further limit the claim from which it depends. Claim 72 depends from claim 49 which limits the fusion partner to a water-soluble polymer. The recitation of a polypeptide is broader in scope than the water soluble polymer recited in claim 49. Thus, claim 72 is not further limiting. 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 Interpretation
Claim 1 is interested to encompass a modified IL-2 polypeptide conjugate comprising a modified IL-2 polypeptide, which 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 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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 10, 36, 49, 53, 58, 72, 78, 111, and 115 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wittrup et al. (WO 2005007121 A1, published January 27, 2005) in view of Ast et al. (WO2012107417 A1, published August 16, 2012).
The claims are drawn to a modified interleukin 2 (IL-2) polypeptide conjugate comprising a modified IL-2 polypeptide, which 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 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.
Wittrup et al. teach a mutant interleukin-2 (IL-2) polypeptide comprising an amino acid sequence of SEQ ID NO:2 and comprising a Y31C mutation (See claim 11 and page 3). Wittrup et al. teach that the IL-2 polypeptide is a chimera (e.g., a fusion protein containing at least a mutant IL-2 polypeptide and a heterologous polypeptide) (See page 17). Wittrup et al. teach that the mutant IL-2 can be fused to a heterologous polypeptide that can increase the circulating half-life of the mutant IL-2 polypeptide, enhance expression of the mutant IL-2 polypeptide, direct cellular localization of the mutant IL-2 polypeptide, or serve as a marker or tag (See page 5). Wittrup et al. teach the heterologous polypeptide is an antibody or an antigen binding fragment thereof, for example, an Fc region of an immunoglobulin (See page 5). Wittrup et al. teach a pharmaceutical composition comprising the mutant IL-2 and a pharmaceutically acceptable carrier (See pages 26-27). Wittrup et al. teach that the reference IL-2 sequence may have a deletion of one or more amino acid residues, for example at position 1, which is interpreted as an N-terminal deletion (See page 15). Wittrup et al. teach that the heterologous polypeptide can be joined at the N-terminus, C-terminus, or both (See page 5).
Wittrup do not teach wherein the IL-2 is conjugated to a water-soluble polymer, a lipid or a polypeptide via a linker.
Ast et al. teach a mutant IL-2 polypeptide comprising the F42A, F42S, or F42K mutation (See page 5). Ast et al. teach that the mutation abolishes or reduces affinity of the mutant IL-2 polypeptide to the high- affinity IL-2 receptor and preserves affinity of the mutant IL-2 polypeptide to the intermediate- affinity IL-2 receptor, each compared to a wild-type IL-2 polypeptide (See page 2). Ast et al. teach that the Phe42Lys (F42K) mutation in IL-2 reduces interaction with CD25 and activation of Treg cells for enhancing efficacy.
Ast et al. teach that the mutant IL-2 polypeptide is linked to a non-IL2 moiety (See page 6). Ast et al. teach that the non-IL-2 moiety comprises albumin or an antibody domain such as Fc domains or antigen binding domains of immunoglobulins (See pages 6 and 28). Ast et al. teach that the components of the immunoconjugate are linked through various linkers, particularly peptide linkers comprising one or more amino acids, typically about 2-20 amino acids (See page 36). Ast et al. teach that suitable linker peptides include (G4S)n, (SG4)n or G4(SG4)n linker peptides (See page 36). Ast et al. teach that chemical modification of the mutant IL-2 may be desirable and teach that problems of immunogenicity and short half-life may be improved by conjugation to substantially straight chain polymers such as polyethylene glycol (PEG) or polypropylene glycol (PPG) (See page 68). Ast et al. teach a pharmaceutical composition comprising the mutant IL-2 polypeptide and a pharmaceutically acceptable carrier (See page 7). Ast et al. teach that the IL-2 mutant may have a deletion, truncation or modification of the wild-type amino acid normally location at that position (See page 8).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the mutant IL-2 polypeptide of Wittrop et al. by linking the heterologous polypeptide via a linker, as taught by Ast et al., because Ast et al. teach that IL-2 can be linked to a non-IL-2 moiety via a linker using linkers known in the art. Further, Ast et al. teach that linking the IL-2 to polymers, such as PEG and PPG, overcome problems of immunogenicity and short-half-life. One of ordinary skill in the art would motivated to construct a modified IL-2 conjugated to a water soluble polymer, such a PEG or PPG, or a polypeptide, such as an Fc domain, for the benefit of reduced immunogenicity and increased half-life when used for therapeutic purposed. One of ordinary skill in the art would have a reasonable expectation of success because the linkers taught by Ast are well-known in the art, and Ast exemplified using a linker to join a heterologous partner to IL-2. Thus, the combination of prior art reference as combined provide a prima facie case of obviousness, absent convincing evidence to the contrary.
It would have been further obvious to one of ordinary skill in the art to modify the mutant IL-2 polypeptide of Wittrop et al. to include a substitution at position F42 because Ast et al. teach that this mutation also abolishes or reduces affinity of the mutant IL-2 polypeptide to the high- affinity IL-2 receptor and preserves affinity of the mutant IL-2 polypeptide to the intermediate- affinity IL-2 receptor, each compared to a wild-type IL-2 polypeptide. One of ordinary skill in the art would be motivated to conjugate comprising a modified IL-2 polypeptide comprising both the Y31C and F42 mutation because doing so would provide a IL-2 polypeptide with abolished or reduced affinity to the high-affinity IL-2 receptor which is responsible for the problems associated with IL-2 immunotherapy.
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". The combination would have yielded a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Thus, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
Claim(s) 1, 36, 49, 53, 58, 72, 78, and 112-115 is/are rejected under 35 U.S.C. 103 as being unpatentable over Wittrup et al. (WO 2005007121 A1, published January 27, 2005) in view of Bossard et al. (WO2012065086A1, published May 18, 2012).
The claims are drawn to a modified interleukin 2 (IL-2) polypeptide conjugate comprising a modified IL-2 polypeptide, which 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 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.
Wittrup et al. teach a mutant interleukin-2 (IL-2) polypeptide comprising an amino acid sequence of SEQ ID NO:2 and comprising a Y31C mutation (See claim 11 and page 3). Wittrup et al. teach that the IL-2 polypeptide is a chimera (e.g., a fusion protein containing at least a mutant IL-2 polypeptide and a heterologous polypeptide) (See page 17). Wittrup et al. teach that the mutant IL-2 can be fused to a heterologous polypeptide that can increase the circulating half-life of the mutant IL-2 polypeptide, enhance expression of the mutant IL-2 polypeptide, direct cellular localization of the mutant IL-2 polypeptide, or serve as a marker or tag (See page 5). Wittrup et al. teach the heterologous polypeptide is an antibody or an antigen binding fragment thereof, for example, an Fc region of an immunoglobulin (See page 5). Wittrup et al. teach a pharmaceutical composition comprising the mutant IL-2 and a pharmaceutically acceptable carrier (See pages 26-27). Wittrup et al. teach that the reference IL-2 sequence may have a deletion of one or more amino acid residues, for example at position 1, which is interpreted as an N-terminal deletion (See page 15). Wittrup et al. teach that the heterologous polypeptide can be joined at the N-terminus, C-terminus, or both (See page 5).
Wittrup do not teach wherein the IL-2 is conjugated to a polymer.
Bossard et al. teach an IL-2 moiety covalently linked to a water soluble polymer (See abstract and paragraphs 0009 and 0072). Bossard et al. teach that the water-soluble polymer is PEG, poly(propylene glycol) ("PPG"), copolymers of ethylene glycol and propylene glycol and the like, poly(oxyethylated polyol), poly(olefmic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(a-hydroxy acid), poly( vinyl alcohol), polyphosphazene, polyoxazolines ("POZ") (which are described in WO 2008/106186), poly(N-aciyloylmorpholine), and combinations of any of the foregoing (See paragraph 0091). Bossard et al. teach that conjugate may be prepared with one or more degradable linkages in the polymer (See paragraph 0104). Bossard et al. teach that the optional features of the conjugate, i.e., the introduction of one or more degradable linkages into the polymer chain or to the IL-2 moiety, may provide for additional control over the final desired pharmacological properties of the conjugate upon administration. For example, a large and relatively inert conjugate (i.e., having one or more high molecular weight PEG chains attached thereto, for example, one or more PEG chains having a molecular weight greater than about 10,000, wherein the conjugate possesses essentially no bioactivity) may be administered, which is released to generate a bioactive conjugate possessing a portion of the original PEG chain. In this way, the properties of the conjugate can be more effectively tailored to balance the bioactivity of the conjugate over time (See paragraph 0107). Bossard et al. teach that the water-soluble polymer can be releasable and releases over time, resulting in unconjugated IL-2 (See paragraph 0108). Bossard et al. teach that IL-2 conjugates comprising a water-soluble polymer have an extended half-life compared to aldesleukin (See paragraph 0235-0236). Bossard et al. teach that IL-2 polymer conjugates exhibit greater tumor growth inhibition and reduced tumor progression than aldesleukin (See paragraphs 0240-0244). Bossard et al. teach that the efficacy in both a lung lesion metastasis model and in a subcutaneous mouse melanoma model was achieved with rIL-2 polymer conjugates at substantially lower frequency of dosing and lower overall protein amount compared to aldesleukin (See paragraphs 0245).
It would have been prima facie obvious before the effective filing date of the claimed invention to modify the mutant IL-2 polypeptide of Wittrup et al. by using a degradable linker to link a water-soluble polymer, such as PEG, to the IL-2 polypeptide, as taught by Bossard et al., because the water-soluble polymer (i.e., PEG) improves the bioactivity of IL-2 and would help the conjugate retain longer half-life compared to unconjugated IL-2 (i.e., aldesleukin). One of ordinary skill in the art would be motivated to do so, and with a reasonable expectation of success, because Bossard et al. teach that linking a water-soluble polymer to IL-2 via a degradable linker allows one to effectively tailor the release of the IL-2 at a specific location, while simultaneously maintaining the bioactivity of the IL-2 once it is released from the water-soluble polymer (i.e., PEG molecule)).
Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses combining prior art elements according to known methods to yield predictable results, thus the combination is obvious unless its application is beyond that person's skill. KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007) also discloses that "The combination of familiar element according to known methods is likely to be obvious when it does no more than yield predictable results". The combination would have yielded a reasonable expectation of success along with predictable results to one of ordinary skill in the art at the time of the invention. Thus, it would have been obvious to a person of ordinary skill in the art to combine prior art elements according to known methods that is ready for improvement to yield predictable results. The claimed invention is prima facie obvious in view of the teachings of the prior art, absent any convincing evidence to the contrary.
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, 36, 49, 53, 58, 72, 78, and 112-115 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 39, 42-43, 45, 60, and 90 of copending Application No. 18/248,729 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claim are drawn to a modified IL-2 polypeptide conjugate comprising a Y31C substitution. Both sets of claims recite that the modified IL-2 polypeptide is conjugated to one or more water-soluble polymers. The ‘729 claims teach modified IL-2 polypeptide is a part of a fusion protein comprising an additional amino acid sequence. The ‘729 claims teach wherein the N terminus or the C terminus of the modified IL-2 polypeptide is fused to an additional amino acid sequence, wherein said additional amino acid sequence comprises an antibody sequence or a portion or a fragment thereof. The ‘729 claims teach wherein the N terminus or the C terminus of the modified IL-2 polypeptide is fused to an additional amino acid sequence, wherein said additional amino acid sequence comprises an Fc portion of an antibody or a portion or a fragment thereof. The ’729 claims teach wherein the modified IL-2 polypeptide is covalently conjugated to the one or more water-soluble polymer(s) comprising polyethylene glycol (PEG) through a linker. Thus, the ‘729 claims anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Status
No claims are allowed.
Conclusion
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/SANDRA CARTER/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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