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
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of PCT/US20/65734 filed on 12/17/2020, which claims the benefit of US Provisional Application No. 62/949,380 filed on 12/17/2019. Claims 3-4 and 6 do not have support in US Provisional Application No. 62/949,380. Specifically, an IL-2 comprising the V91K mutation and an anti-OX40 agonist antibody comprising SEQ ID NOs: 9 and 10 are not taught in US Provisional Application No. 62/949,380. Therefore, Claims 3-4 and 6 receive an effective filing date of 12/17/2020. All other claims receive an effective filing date of 12/17/2019.
Election/Restriction
Applicant’s election of Group I, directed to an IL-2 chimeric molecule, in the reply filed on July 8, 2025 and the species election of B) V91K in the phone call received from Dr. David Roadcap on August 7, 2025 is acknowledged (see attached interview summary). Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 17, 19-21, 23-35 are withdrawn from further consideration pursuant
to 37 CFR 1.142(b), as being drawn to a nonelected inventions or species, there being no allowable generic or linking claim. Election was made without traverse in the written reply filed on July 8, 2025 and the phone call received on August 7, 2025.
Claim Status
Claim listing filed on July 8, 2025 is pending. Claims 5, 7-16, 18, and 22 are canceled. Claims 1, 3, and 6 are amended. Claims 17, 19-21, 23-35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected species. Claims 1-4 and 6 are examined upon their merits.
Information Disclosure Statement
The information disclosure statements filed on 05/15/2025 and 10/13/2022 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities: The title at the top of the specification recites “DUAL INTERLEUKIN-2/TNF RECEPTOR AGONSIT FOR USE IN THERAPY” which is not consistent with the title listed on the Application Data Sheet filed on June 16, 2022 which recites “INTERLEUKIN-2 IN COMBINATION WITH TNF RECEPTOR FAMILY MEMBERS FOR THE EXPANSION OF T-REGULATORY CELLS.” 37 C.F.R. 1.72 states “Unless the title is supplied in an application data sheet, the title of the invention should appear as a heading on the first page of the specification.” It is unclear which title is the intended title due to the inconsistency between the Application Data Sheet and the specification.
Appropriate correction is required, especially considering that the two titles have different meanings.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Specifically, there is a hyperlink in the last line on page 11. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Applicant is urged to carefully review the specification for additional informalities.
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.
Claims 1-4 and 6 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites a human IL-2 chimeric molecule comprising a human IL-2 polypeptide comprising an amino acid sequence at least 70% identical to the sequence set forth in SEQ ID NO: 1 and an anti-OX40 agonist antibody. The IL-2 polypeptide can comprise at least 95% identity to the sequence set forth in SEQ ID NO: 1 (Claim 2). The anti-OX40 agonist antibody can have heavy and light chains comprising SEQ ID NOs: 9 and 10, respectively (Claim 6). Note, “an amino acid sequence set forth in” encompasses any fragment of two or more amino acid residues within the recited sequence. The language of “70% identity” and “an amino acid sequence set forth in” encompasses a genus of thousands of possible IL-2 variations. The possible mutation combinations listed in Claim 3 exemplify only a portion of the genus of IL-2 variants encompassed by the claims. Applicant could amend the claim language to “the amino acid sequence of SEQ ID NO: 1” or “the amino acid sequence comprising SEQ ID NO: 1” to claim the entire SEQ ID NO: 1 sequence instead of fragments within SEQ ID NO: 1.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. In order to provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
In the instant case, an IL-2 polypeptide having at least 70% or 95% identity to the sequence set forth in SEQ ID NO: 1 results in a genus of possible chimeric molecules. Any combination of IL-2 residues could be inserted, deleted, or substituted with conservative or non-conservative changes as long as at least 70% sequence identity to any sequence set forth in SEQ ID NO: 1 is maintained (as taught in specification pages 5 and 10). The broadness of these claims encompasses thousands of chimeric molecule variations.
From the specification, a chimeric molecule as shown in Figure 6 Molecule #3 was generated and induced preferential expansion of Treg cells when administered to mice (Example 2, page 42). However, Molecule #3 comprises a mouse IL-2 comprising residues 21-169 and mutations T23A, P71T, and C160A (Figure 6). This example of IL-2 provides written description for a single mouse IL-2 variant, but does not provide sufficient description for the genus of possible human IL-2 variants encompassed by the claims.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (MPEP § 2163.05.Ib). Describing one IL-2 variant in a different species with different amino acid mutations and without distinguishing structure-to-function attributes does not provide adequate written description of the claimed genus of human IL-2 variants.
Further, no evidence is provided that the anti-OX40 antibody comprising SEQ ID NOs: 9 and 10 binds and agonizes OX40. In the only experiment with the antibody as a single agent, no Treg cell proliferation was observed (Example 1 and Figure 2 description). The anti-OX40 antibody comprising SEQ ID NOs: 9 and 10 was not described in such a way that one of ordinary skill would understand that the inventor was in possession of an antibody that both binds and agonizes OX40.
There is insufficient written description for the IL-2 variants and for the anti-OX40 agonist antibody comprising SEQ ID NOs: 9 and 10, and neither of these deficiencies are overcome when the two parts are combined in a chimeric molecule. Therefore, Claims 1-4 and 6 are rejected for insufficient written description.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claims 1-4 and 6 are also rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a chimeric molecule comprising an IL-2 polypeptide comprising SEQ ID NO: 1 with mutations V91K and C125A and an anti-OX40 agonist antibody known in the art prior to filing, does not reasonably provide enablement for the genus of IL-2 polypeptides comprising at least 70% identity to the amino acid sequence set forth in SEQ ID NOs: 1 (Claims 1-4) nor the anti-OX40 agonist antibody comprising SEQ ID NOs: 9-10 (Claim 6). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
MPEP § 2164.01(a) states that there are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure
does not satisfy the enablement requirement and whether any necessary experimentation is
“undue”. These factors include, but are not limited to:
A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims and nature of the invention:
The nature of the invention is complex. As understood with the broadest reasonable interpretation, the claims encompass an IL-2 chimeric molecule comprising a human IL-2 polypeptide comprising an amino acid sequence at least 70% or at least 95% identical to the sequence set forth in SEQ ID NO: 1 and an anti-OX40 agonist antibody (Claims 1-2). The anti-OX40 agonist antibody can have heavy and light chains comprising SEQ ID NOs: 9 and 10, respectively (Claim 6). The language of “70% identity” and “an amino acid sequence set forth in” encompasses a genus of thousands of possible IL-2 variations. From the specification (pages 5 and 10), any combination of residues could be inserted, deleted, or substituted with conservative or non-conservative changes in the IL-2 polypeptide as long as at least 70% or at least 95% sequence identity is maintained to the sequence set forth in SEQ ID NO: 1. The possible mutation combinations listed in Claim 3 only exemplify a portion of the genus of IL-2 variants encompassed by the claims.
When analyzing the scope of enablement, the claims are analyzed with respect to the teachings of the specification and are to be "given their broadest reasonable interpretation consistent with the specification." See MPEP 2111 [R-5]; Phillips v. AWH Corp., 415 F.3d 1303, 75 USPQ2d 1321 (Fed. Cir. 2005); and In re Hyatt, 211 F.3d 1367, 1372, 54 USPQ2d 1664, 1667 (Fed. Cir. 2000). Applicant always has the opportunity to amend the claims during prosecution, and broad interpretation by the examiner reduces the possibility that the claim, once issued, will be interpreted more broadly than is justified. In re Prater, 415 F.2d 1393, 1404-05, 162 USPQ 541, 550- 51 (CCPA 1969).
The state of the prior art and level of predictability in the art:
The level of predictability in the art depends, most importantly, on whether the claimed invention can be practiced by one of ordinary skill in the art. Li et al. US 2022/0170028 (effectively filed June 14, 2019) teaches the sequence of human IL-2 is SEQ ID NO: 2 which is 100% identical to instant SEQ ID NO: 1 (page 40). Li further teaches that C125A is widely used in recombinant IL-2 to avoid an unpaired cysteine at position 125, and the C125A variant retains full biological activity (paragraph [0226]). Li uses IL-2 comprising a V91K mutation as a benchmark control (Benchmark-1) with which to compare other IL-2 mutations that demonstrate preferential Treg activation (paragraph [0236] and Figs. 5E-F) which shows that the V91K mutation was known to preferentially stimulate Treg cells before the effective filling date of the instant invention. Li shows that the state of the art at the time of filing is enabling for an IL-2 comprising SEQ ID NO: 1 and mutations V91K and C125A that preferentially stimulates Treg cells, but is not enabling for the genus of IL-2 variants encompassed by the claims.
Liu et al. US 9,006,399 (published April 14, 2015) teaches that humanized anti-OX40 agonist antibodies were known in the art prior to the time of filing (Abstract and Claims 1-8). However, an anti-OX40 agonist antibody comprising SEQ ID NOs: 9 and 10 was unknown in the art at the time of filing. The art enables a human anti-OX40 agonist antibody (Claims 1-4) but not an anti-OX40 agonist antibody specifically comprising SEQ ID NOs: 9 and 10.
Level of skill in the art:
The level of skill would be high encompassing fusion protein science, antibodies, cytokines, immunology, binding assays, etc.
Amount of direction provided by inventor and the existence of working examples:
The specification only evaluates one chimeric molecule as shown in Figure 6 Molecule #3 which induced preferential expansion of Treg cells when administered to mice (Example 2, page 42). Molecule #3 comprises a mouse IL-2 comprising residues 21-169 and mutations T23A, P71T, and C160A (Figure 6). However, one representative mouse IL-2 variant is not sufficient to enable the genus of possible human IL-2 variants encompassed by the claims, especially those that preferentially stimulate Treg cells. A person having ordinary skill in the art would have to make a substantial inventive contribution in order to make and characterize a representative number of chimeric molecules comprising different IL-2 species to encompass the claimed genus.
Further, no evidence is provided that the anti-OX40 antibody comprising SEQ ID NOs: 9 and 10 binds and agonizes human OX40. The only experiment evaluating the antibody as a single agent induced no Treg cell proliferation (Example 1 and Figure 2 description). There is no evidence that an antibody comprising SEQ ID NOs: 9 and 10 binds and agonizes human OX40, and further experimentation by one of ordinary skill would be required to determine the antibody’s functional properties.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
In light of the unpredictability surrounding the claimed subject matter, the undue breadth of the claimed invention’s intended use, and the lack of adequate guidance, one wishing to make and use the presently claimed invention would be unable to do so without engaging in undue experimentation. The specification is not enabling for the genus of IL-2 variants nor for the anti-OX40 agonist antibody comprising SEQ ID NOs: 9 and 10, and neither of these deficiencies are overcome when the two parts are combined in a chimeric molecule. Given that structure is essential to function, a person having ordinary skill in the art would have to perform further experimentation to systematically make the chimeric molecule variants encompassed by the claims and screen their individual characteristics in order to practice the invention commensurate with the scope of the claims.
The instant specification does not enable the invention to make and use the entire genus of chimeric molecules; therefore, Claims 1-4 and 6 are rejected.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claim 6 is rejected under 35 U.S.C. 101 because the disclosed invention is inoperative and therefore lacks utility. Claim 6 is directed to a chimeric molecule comprising an IL-2 variant and an anti-OX40 agonist antibody comprising SEQ ID NOs: 9 and 10. There are no examples in the specification that teach that an antibody comprising SEQ ID NOs: 9 and 10 is capable of binding and agonizing OX40. The only experiment evaluating the antibody as a single agent induced no Treg cell proliferation (Example 1 and Figure 2 description), and the state of the art prior to filing teaches that an anti-OX40 agonist antibody increases Treg proliferation (Ruby et al. J Immunol. 2009; page 4, paragraph 2). Therefore, a chimeric molecule comprising an antibody comprising SEQ ID NOs: 9 and 10 does not operate to produce the results claimed by the patent application (binding and agonizing OX40), and Claim 6 is rejected for lack of utility.
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.
Claims 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. US 2022/0170028 (effectively filed June 14, 2019), and further in view of Ruby et al. J Immunol. 2009.
The instant claims are directed to a human IL-2 chimeric molecule comprising a human IL-2 polypeptide comprising an amino acid sequence at least 70% or at least 95% identical to the sequence set forth in SEQ ID NO: 1 and an anti-OX40 agonist antibody (Claims 1-2). Claim 3 recites wherein the IL-2 polypeptide is a mutein that comprises the V91K and preferentially stimulates Treg cells. It is interpreted that preferentially stimulating Treg cells is an inherent property of IL-2 polypeptides that comprise the V91K mutation (MPEP § 2112.01.I-II). The specification defines “preferentially stimulates T regulatory cells” to mean that the mutant promotes survival, activation, and/or function of CD3+FoxP3+ T cells over CD3+FoxP3- T cells that can be measured by methods known in the art such as flow cytometry (page 6, paragraph 2). Claim 4 recites “the human IL-2 chimeric molecule of claim 3, further comprising a substitution at C125A” which is interpreted as the IL-2 polypeptide mutant defined in claim 3 further comprises a C125A mutation.
Li teaches that delivering an IL-2 variant that preferentially expands Treg cells at the intended site of therapy (ie an immunocytokine) has the potential to further enhance existing responses of therapies for various autoimmune and inflammatory diseases (paragraph [0285]). Li specifically constructed antibody-IL-2 fusion proteins that build upon the IL-2 variants with biased selectivity for Tregs as disclosed in the application (paragraph [0286] and Table 8). The antibodies can bind a plethora of anti-inflammatory targets such as α4β7, β7, MAdCAM-1, BAFF, TNFα, or IL-6Rα (paragraph [0286]). The IL-2 polypeptide can comprise SEQ ID NO: 2 which is 100% identical to instant SEQ ID NO: 1 (page 40). IL-2 comprising V91K is used as a benchmark control (Benchmark-1) with which to compare other IL-2 mutations that demonstrate preferential Treg activation (paragraph [0236] and Figs. 5E-F) which shows that the V91K mutation is understood to preferentially stimulate Treg cells. Li further teaches that C125A is widely used in recombinant IL-2 to avoid an unpaired cysteine at position 125, and the C125A variant retains full biological activity (paragraph [0226]).
Li fails to teach wherein the antibody-IL-2 fusion protein specifically comprises an anti-OX40 agonist antibody.
Ruby teaches that Tregs constitutively express OX40 on their surface (Introduction paragraph 1), and a single injection of αOX40 (an agonist OX40 antibody) in mice increased the numbers of FoxP3+ Tregs four-fold as compared to controls (page 4, paragraph 2).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to substitute the antibody in the antibody-IL-2 fusion proteins taught by Li with an anti-OX40 agonist antibody taught by Ruby. Li teaches that antibody-IL-2 fusion proteins can deliver variant IL-2 polypeptides that preferentially stimulate Tregs to therapeutic sites as a treatment for various autoimmune and inflammatory diseases. Li also teaches that the antibody can be any anti-inflammatory target of interest. Because Ruby teaches that anti-OX40 agonist antibodies target Tregs and promote their proliferation, it would be obvious to use the anti-OX40 agonist antibodies in the IL-2 fusion proteins wherein the IL-2 variant also stimulates Tregs. Li teaches that the motivation to combine known anti-inflammatory antibodies with Treg cell-selective IL-2 variants is to enhance the therapeutic index of cytokines and provide targeted drug delivery in the treatment of autoimmune and inflammatory diseases (paragraph [0285] and Table 8).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH COOPER PATTERSON whose telephone number is (703)756-1991. The examiner can normally be reached Monday - Friday 8:00am - 5:00pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at (571) 272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675