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 .
Election/Restrictions
Applicant’s election without traverse of Group I (i.e., Claims 21-26 and 31-36, drawn to a T-cell modulatory polypeptide (TMP)) and to Species A (i.e., A single and specific T-Cell modulatory polypeptide indicating the following: 1. Single and specific Ig Fc polypeptide, Applicants’ election: SEQ ID NO: 30 (L234A/L235A; “LALA); 2. Single and specific amino acid sequence corresponding to HLA-A polypeptide, Applicants’ election: SEQ ID NO: 233 (HLA-A11 (Y84C; A236C); 3. Single and specific KRAS peptide epitope sequence indicating the length and sequence identifier, Applicants’ election: SEQ ID NO 179, length 10 (VVVGADGVGK); 4. Whether the TMP comprises a heterodimeric polypeptide, one single chain polypeptide or two single chain polypeptides, and whether the components in the TMP are linked to one or more linkers, and if so a single and specific linker including indication of linker location, Applicants’ election: single chain, components are linked as such: A236C forms a disulfide bond with R12C; and Y84C forms a disulfide bond with G2C); in the reply filed on 02/05/2026 is acknowledged. Because Applicants 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Claims 27-30 and 37-40 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention; and claims 22-25, 33-35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species; there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/05/2026.
Please note that the elected species do not read on the claims. For instance SEQ ID NO: 30 with substitutions at L234A/L235A was elected as the single Ig Fc polypeptide. However, claim 22 does not recite substitutions at positions L234A/L235A. The same is true for SEQ ID NO: 233 elected as the single and specific amino acid sequence corresponding to HLA-A polypeptide, however, claim 24 does not encompass the elected sequence, etc.
Claim Status
Claims 1-20 were originally filed on 10/01/2024.
The amendment filed on 12/13/2024 cancelled claims 1-20 and added new claims 21-40.
Claims 21-40 are currently pending and claims 21, 23, 25-26, 31-32, 35 are under consideration.
Priority
The present application is a CON of 17/584,133 filed on 01/25/2022, which is a CON of PCT/US2020/051255 filed on 09/17/2020, which claims benefit of 62/903,441 filed on 09/20/2019,
and claims benefit of 62/990,693 filed on 03/17/2020, and claims benefit of 63/048,561 filed on 07/06/2020. Applicants’ claim for the benefit of a prior-filed application under 35 U.S.C 119 (e) or under 35 U.S.C 120, 121, or 365 (c ) is acknowledged.
Information Disclosure Statement
The Information Disclosure Statements (IDSs) filed on 12/13/2024, 02/28/2025, 04/03/2025, 06/16/2025 and 09/25/2025 have been considered by the Examiner.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code at pg. 56, para[00194]. 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.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
In the instant case, Figures 3A to 11; Figures 13A to 15JJ; Figures 19A-19P depict sequences which lack a sequence identification number. Please note that the specification and the Figures have not been checked to the extent necessary to determine the presence of all possible error. Applicants’ cooperation is required in correcting any errors of which Applicant may become aware in the specification and the drawings.
Drawings
The drawings are objected to because the drawings do not include a sequence identification number (see Figures 3A to 11; Figures 13A to 15JJ; Figures 19A-19P). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Interpretation
For purposes of applying prior art, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation set forth below, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
For claim 21, regarding the scope of “heterodimeric polypeptide”, it is noted that the instant specification does not define what constitutes a “heterodimeric” polypeptide. Pursuant to MPEP 2111.01, under a broadest reasonable interpretation, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. The plain meaning of a term means the ordinary and customary meaning given to the term by those of ordinary skill in the art at the time of the invention. Biology Insights defines a “heterodimer” as a molecular complex formed when two different subunits, join together to perform a specific function. The term combines “hetero” meaning different, with “dimer” referring to two parts. These distinct subunits assemble into a single, functional entity, allowing for varied capabilities (see Biology Insights, published online July 24, 2025 at https://biologyinsights.com/heterodimer-function-formation-and-biological-roles/, accessed on 04/10/2026). As such, the scope of “heterodimeric” polypeptide is being interpreted as encompassing a polypeptide comprising two different/distinct subunits, wherein the two different subunits constitute a first polypeptide (i.e., subunit one) comprising KRAS peptide epitope-Cys-containing linker-ß2M); and a second polypeptide (i.e., subunit two) comprising MHC-one or more IL-2 polypeptides-immunoglobulin Fc polypeptide.
Additionally, with respect to the TMP comprising at least one heterodimeric polypeptide, it is noted that claim 21 does not recite a function associated with the at least one heterodimeric polypeptide. As such, given the disclosure the first polypeptide and second polypeptide that constitute the at least one heterodimeric polypeptide (i.e., KRAS peptide epitope, ß2M polypeptide, Cys-containing linker, MHC class I heavy chain polypeptide, IL-2 polypeptide variant represented by SEQ ID NO: 241, and an immunoglobulin (Ig) Fc polypeptide) and combined with the pre-existing knowledge in the art regarding the genetic code and its redundancies, an ordinary skilled artisan would have put one in possession of the genus of TMP comprising at least one heterodimeric polypeptide as claimed. With the aid of a computer, an ordinary skilled artisan could have identified all the components of the instantly claimed heterodimeric polypeptide comprised by the TMP. Thus, an ordinary skilled artisan would conclude that the applicant was in possession of the claimed genus at the time the application was filed.
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.
1. Claims 21, 26, 31-32 and 36 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 21 is drawn to a T-cell modulatory polypeptide (TMP) comprising at least one heterodimeric polypeptide, wherein the at least one heterodimeric polypeptide comprises: […] iii) a cys-containing linker that joins the KRAS peptide epitope to the ß2M polypeptide […] wherein one or more independently selected linkers may be interposed between any two of the components of the second polypeptide […]. However, the instantly claimed TMP only comprises one linker, i.e., Cys-containing linker, comprised by the first polypeptide. Therefore an ordinary skilled artisan would not be able to ascertain the metes and bounds of the claimed invention with respect to the one or more independently selected linkers that may be interposed between any two of the components of the second polypeptide, because it has not been clearly established whether the second polypeptide comprises any linkers and whether the supposedly one or more independently selected linkers are the same or different to the only linker comprised by the first polypeptide (i.e., Cys-containing linker). Therefore, the claim limitations recited in instant claim 21 fail to define or particularly point out and distinctly claim the subject matter which the inventor regards as the invention, because the recitation implies that the one or more linkers have been previously selected and is/are different from the only cys-containing linker claimed. Claims 26, 31-32 and 36 are rejected because of their dependency.
2. Claim 26 is 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 26 depends from parent claim 21, therefore, the claim limitations recited in claim 21 also apply to claim 26. Therefore, the “two identical heterodimeric polypeptides” fail to further limit the scope of parent claim 21, because as discussed in the “Claim Interpretation” section above, the scope of a heterodimeric polypeptide encompasses two different/distinct subunits which constitute a first polypeptide and a second polypeptide. Thus, two identical polypeptides cannot form a “heterodimeric polypeptide”. Therefore, one of ordinary skill in the art would be unable to ascertain the meets and bounds of the invention with regards to the TMP comprising two identical heterodimeric polypeptides linked together by one or more disulfide bonds between the Ig Fc of the first heterodimeric polypeptide and the Ig Fc of the second heterodimeric polypeptide.
3. Claims 31-32 and 36 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 31 recites the limitation “wherein one or more independently selected linkers may be interposed between any two of the components of the single-chain polypeptide.” In lines 9-10. There is insufficient antecedent basis for this limitation in the claim, because prior to the recitation of the quoted limitation, the claim is silent one or more linkers and/or their placement in relation to the components of the single-chain polypeptide. Claims 32 and 36 are rejected because of their claim dependency.
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.
4. Claim 26 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. Claim 26 is directed to two identical heterodimeric polypeptides. However, claim 26 is dependent upon claim 21, which is directed to a TMP comprising at least one heterodimeric polypeptide. As discussed in the “Claim Interpretation” section above, a heterodimer is defined as complex formed when two different subunits, join together to perform a specific function. As such, when the TMP comprises two identical polypeptides covalently linked together by one or more disulfide bonds between the Ig Fc of the first polypeptide and the Ig Fc of the second polypeptide, a heterodimeric polypeptide cannot be formed. Thus the scope of claim 26 broadens the scope of parent claim 21. Applicant may cancel the claims, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Please note that the Examiner is interpreting the scope of claim 26 in a manner similar to claim 21 in the 112(b) rejection above where a first different/distinct polypeptide and a second different/distinct polypeptide are assembled into a single TMP in order to advance prosecution.
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.
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.
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness
(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
5. Claims 21, 26, 31-32 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0282392A1 Pub. Date: Oct. 4, 2018 (cited in the IDS filed on 12/13/2024) (herein after “392”), in view of US 2018/0086832 A1 Pub. Date: Mar. 29, 2018 (cited in the IDS filed on 12/13/2024)(herein after “832”); and WO2018/119114 A1 International Pub. Date: June 28, 2018 (cited in the IDS filed on 12/13/2024)(herein after “114”), as evidenced by GenCore Sequence Alignment instant SEQ ID NO: 241 v SEQ ID NO: 38, pp. 1 (herein after “GenCore”).
Regarding claim 21, ‘392 teaches multimeric polypeptides comprising an immunomodulatory domain at the C-terminus of the first polypeptide or at the N-terminus of the second polypeptide (see pg. 4, para[0033]). The multimeric polypeptide taught by ‘392 comprises at least a first polypeptide and a second polypeptide where the first polypeptide comprises, in order from N-terminus to C-terminus: i) an epitope; and ii) a first major histocompatibility complex (MHC) polypeptide; and where the second polypeptide comprises, in order from N-terminus to C-terminus: i) a second MHC polypeptide; and ii) an immunoglobulin (lg) Fc polypeptide (see pg. 4, para[0033]). ‘392 also teaches that sometimes the multimeric polypeptide comprises a ß2-Microgrobulin peptide as the first MHC polypeptide and the second MHC polypeptide is an MHC class I heavy chain polypeptide (see pg. 4, para[0034]); additionally that in some cases the epitope is a T-cell epitope (see pg. 4, para[0034]).
‘392 describes that the epitope peptide bound by a first amino acid linker sequence contiguous with a sequence of amino acids comprising a sequence identical to a human native ß2M peptide sequence, wherein (i) is bound by one, or more than one, disulfide bond to (ii) a T cell modulatory domain peptide contiguous with a second amino acid linker sequence contiguous with a sequence of amino acids having the sequence of a MHC heavy chain contiguous a third amino acid linker sequence contiguous with a sequence of amino acids identical to an immunoglobulin Fc domain (see pg. 4, para[0032]).
And that in some cases the first MHC polypeptide or a linker between the epitope and the first MHC polypeptide comprises an amino acid substitution to provide a first Cys residue, and the second MHC polypeptide comprises an amino acid substitution to provide a second Cys residue, and wherein the disulfide linkage is between the first and the second Cys residues (see pg. 5, para[0034]). ‘392 also describes that the multimeric polypeptide comprises a first linker interposed between the epitope and the first MHC polypeptide (see pg. 5, para[0034]).
Thereby the teachings of ‘392 correspond to a Cys-containing linker that joins the peptide epitope to the ß2M polypeptide, as well as to wherein one or more independently selected linkers may be interposed between any two of the components of the second polypeptide as recited in instant claim 21. Thus, the teachings of ‘392 read on the claim limitations recited in instant claim 21, wherein the TMP comprises at least one heterodimeric polypeptide, wherein the at least one heterodimeric polypeptide comprises a) a first polypeptide comprising ii) a ß2-microglobulin polypeptide, and iii) a Cys-containing linker that joins the peptide epitope to the ß2M polypeptide; and b) a second polypeptide comprising i) a major histocompatibility complex (MHC) class I heavy chain polypeptide, and iii) an immunoglobulin (Ig) Fc polypeptide.
However, ‘392 does not expressly teach i) a KRAS peptide epitope comprising a KRAS epitope expressed on a cancer cell, ii) one or more variant IL-2 polypeptides, wherein the one or more variant IL-2 comprise the amino acid sequence set forth in SEQ ID NO: 241.
‘832 teaches that mutant epitopes encoded by cancer genes are virtually always located in the interior of cells, making them invisible to conventional antibodies. Thus, ‘832’s invention pertains to the generation of single chain variable fragments specific for mutant peptides presented on the cell surface by human leukocyte antigen (HLA) molecules (see abstract). ‘832 also teaches that 10% to 20% of the epitopes created by mutant genes in cancers are predicted to bind to common HLA types, as disclosed in the literature reviewed by ‘832 (see pg. 1, para[0004]).
In particular, ‘832 claims an isolated molecule comprising an antibody variable region which specifically binds to a complex of a human leukocyte antigen (HLA) molecule and a peptide which is a portion of a protein, wherein the peptide comprises a mutant residue, and wherein the mutant residue is in an intracellular epitope of the protein (see pg. 33, claim 1). ‘832 also claims that the complex further comprises a ß-2-microglobulin molecule (see pg. 33, claim 2).
‘832 adds that mutations in oncogenes and tumor suppressor genes drive tumorigenesis, and their protein products form therapeutic targets that are absent from normal cells; and that nearly all such mutant epitopes lie in the interior of the cells, either in the cytoplasm or nucleus, complicating immunotherapies directed against the mutants (see pg. 3, para[0035]). ‘832 adds that the inventive approach may be used not solely for tumor suppressors and oncogenes, but also passenger mutations (not drivers of carcinogenesis) as well as for other proteins that are the product of somatic mutagenesis or which are expressed on cell surfaces as the result of somatic mutagenesis (see pg. 3, para[0035]). Therefore, ‘832’s invention overcomes the shielding of intracellular targets lying within cells by targeting forms that are displayed on the surface of cells (see pg. 3, para[0035]). Some examples of the intracellular proteins which may be targeted include KRAS, additionally ‘832 taches that is also desirable to select mutations that are prevalent in cancer populations such as KRAS G12, KRAS G13; and common mutants such as KRAS G12V, KRAS G12C, KRAS G12D (see pg. 5, para[0036]).
Moreover, ‘832 teaches that by using a procedure for generating scFvs (single chain variable fragments) that selectively bind to mutant peptides embedded within HLA-beta-2 microglobulin complexes; scFvs against the products of two commonly mutated oncogenes (KRAS and EGFR) when
complexed with two common HLA types (A2 and A3, respectively) were obtained (see pg. 4, para[0042]). These scFvs bind to the peptide-HLA complexes on the surface of cells and can kill those cells when complement is present (see pg. 4, para[0042]).
Therefore 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 modify ‘392’s multimeric polypeptide with the teachings of ‘832 in order to arrive at the claimed TMP comprising a KRAS peptide epitope comprising a KRAS epitope expressed on a cancer cell. One of ordinary skill in the art would have been motivated to do so because it was known that 10% to 20% of the epitopes created by mutant genes in cancers are predicted to bind to common HLA types; because mutant epitopes encoded by cancer genes are virtually always located in the interior of cells, making them invisible to conventional antibodies thus complicating immunotherapies directed against the mutants; and because intracellular proteins such as KRAS comprising mutations are prevalent in cancer populations as taught by ‘832. One of ordinary skill in the art before the effective filing date of the claimed invention would have had a reasonable expectation of success given that ‘832’s single chain variable fragments against the commonly mutated oncogene KRAS when embedded within HLA-ß2M complexes bind to the peptide-HLA complexes on the surface of cells and can kill those cells when the complement is present, thus overcoming the shielding of intracellular targets found within cells (i.e., in the interior of the cells, either in the cytoplasm or nucleus) because forms of the mutant peptide (i.e., KRAS epitope) presented on the cell surface are targeted instead. Additionally, one of ordinary skill in the art would have had a reasonable expectation of success given that the multimeric polypeptide of ‘392 comprises a T-cell modulatory domain peptide and that the epitope is a T-cell epitope. Therefore, substituting ‘392’s epitope peptide (i.e., T-cell epitope) with ‘832’s KRAS peptide would support the instantly claimed TMP by constituting a simple substitution of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, pursuant to KSR.
With respect to ii) one or more variant IL-2 polypeptides, wherein the one or more variant IL-2 comprise the amino acid sequence set forth in SEQ ID NO: 241, as recited in instant claim 21:
‘114 is in the field of T-cell modulatory multimeric polypeptides and methods of use thereof (see front pg., Title). ‘114 invention pertains to variant immunomodulatory polypeptides and provides methods of modulating the activity of a T-cell, such methods comprise contacting the T cell with a T-cell modulatory multimeric polypeptide (see pg. 10, para[0067]). ‘114 also teaches that when the target T cell is a CD8+ T cell, the multimeric polypeptide comprises Class I MHC polypeptides (e.g., ß2-microglobulin and Class I MHC heavy chain) (see pg. 106, para[00224]).
‘114 describes that that the multimeric polypeptide functions as a surrogate antigen presenting cell (APC) and mimics the adaptive immune response by engaging a T cell receptor (TCR) present on the surface of a T cell with an epitope-presenting peptide complexed with an MHC present in the multimeric polypeptide (see pg. 10, para[0068]). This engagement provides the multimeric polypeptide with the ability to achieve epitope-specific cell targeting (see pg. 10, para[0068]). ‘114 adds that the multimeric polypeptide also possesses at least one immunomodulatory protein (MOD) that engages a counterpart costimulatory protein on the T-cell and that the immunomodulatory protein may be a variant of a naturally occurring immunomodulatory protein (e.g., naturally occurring IL-2), which variant exhibits a reduced affinity for its counterpart costimulatory protein on the T cell (e.g., IL-2R) as compared to the affinity of the naturally occurring immunomodulatory protein for the counterpart costimulatory protein (see pg. 10, para[0068]).
For example, a multimeric polypeptide is contacted with a population of T cells comprising: i) a target T cell(s) that is specific for the epitope present in the multimeric polypeptide; and ii) a non-target T cell(s), e.g., a T cell(s) that is specific for a second epitope(s) that is not the epitope present in the multimeric polypeptide (see pg. 105, para[00230]). Contacting the population results in selective delivery of the costimulatory polypeptide(s) (e.g., naturally occurring costimulatory polypeptide (e.g., naturally occurring IL-2) or reduced-affinity variant of a naturally occurring costimulatory polypeptide (e.g., an IL-2 variant)), which is present in the multimeric polypeptide, to the target T cell (see pg. 105, para[00230]). Thus, e.g., less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 4%, 3%, 2% or 1 %, of the non-target T cells bind the multimeric polypeptide and, as a result, the costimulatory polypeptide (e.g., IL-2 or IL-2 variant) is not delivered to the non-target T cells (see pg. 105, para[00230]).
Furthermore, ‘114 also teach that in some instances the epitope-specific T cell is a T cell that is specific for an epitope present on a cancer cell, and contacting the epitope-specific T cell with the multimeric polypeptide increases cytotoxic activity of the T cell toward the cancer cell (see pg. 106, para[00225]).
‘114 teaches Figures 2B-2Q, which depict amino acid sequences of variant IL-2 polypeptides (see pg. 2, para [0006] and FIG. 2B-2Q). A sequence alignment of amino acid sequence corresponding to a variant IL-2 represented SEQ ID NO: 241 and ‘114’s SEQ ID NO: 38 depicted in Fig. 2B reveals a 98.5% identity (see GenCore, Sequence alignment). Thus ‘114 IL-2 variant reads on ii) one or more variant IL-2 polypeptides, as recited in instant claim 21.
From the teachings of the references, the Examiner recognizes that 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 incorporate an IL-2 variant polypeptide as taught by ‘114 as part of the multimeric polypeptide taught by ‘392 in order to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to do so because it was known that a variant of a naturally occurring immunomodulatory protein (i.e., IL-2) exhibits a reduced affinity for its counterpart costimulatory protein on the T cell (e.g., IL-2R) thereby less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 4%, 3%, 2% or 1 %, of the non-target T cells bind the multimeric polypeptide comprising the IL-2 variant, and as a result, the costimulatory polypeptide (e.g., IL-2 or IL-2 variant) is not delivered to the non-target T cells; because it was also known that contacting the epitope-specific T cell with the multimeric polypeptide increases cytotoxic activity of the T cell toward the cancer cell as taught by ‘114.
One of ordinary skill in the art would have had a reasonable expectation of success given that ‘114 teaches that when the target T cell is a CD8+ T cell, the multimeric polypeptide comprises Class I MHC polypeptides (e.g., ß2-microglobulin and Class I MHC heavy chain); and given that the IL-2 variant represented by SEQ ID NO: 38 as taught by ‘114 comprises the amino acid sequence set forth in instant SEQ ID NO: 241. Therefore, incorporating an IL-2 variant polypeptide as part of the multimeric polypeptide of ‘392 would support the instantly claimed TMP comprising one or more variant IL-2 polypeptides by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, pursuant to KSR.
Regarding claim 26, ‘392 describes that the multimeric polypeptide can be a homodimer, where two molecules of the multimeric polypeptide are present in the homodimer, and can be disulfide linked to one another, e.g., via the Fc polypeptide present in the two molecules (see pg. 14, para[0117]). Thereby the teachings of ‘392 read on the claim limitations recited in instant claim 26, wherein the TMP comprises two identical heterodimeric polypeptides, and wherein the heterodimeric TMPs are covalently linked together by one or more disulfide bonds between the Ig Fc of the first heterodimeric polypeptide and the Ig Fc of the second heterodimeric polypeptide.
Regarding claims 31, ‘392 depicts Fig. 19A which illustrates constructs described in relation to FIG. 2A - 2C respectively (see pg. 9, para[0062]). For convenience, ‘392’s Figure 19A is reproduced herewith (i.e.
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). With respect to FIG . 2A - 2C: The synTac Fc - fusion construction. One strategy exploits an Fc - fusion construction to increase the valency, stability and therapeutic window of the associated products. Briefly, the Fc region is a native covalent homo-dimer , formed through interaction of two identical immunoglobulin CH2 - CH3 domains (termed Fc) and stabilized through two disulfide bonds between the CH2 domains, illustrated as two thin lines (see pg. 7, para[0046]). Thus ‘392’s depiction of a single chain construct reads on an epitope, a ß2M polypeptide, a MHC heavy chain polypeptide; a immunoglobulin (Ig) Fc polypeptide.
However, ‘392 does not expressly teach wherein i) the epitope is a KRAS peptide epitope comprising a KRAS epitope expressed on a cancer cell; nor wherein v) one or more variant IL-2 polypeptides, wherein the one or more variant IL-2 comprise the amino acid sequence set forth in SEQ ID NO: 241, as recited in instant claim 31.
As previously discussed above for claim 21, an ordinary skilled artisan would have been motivated with reasonable expectation of success after reading ‘832 to substitute ‘392’s epitope with a KRAS epitope commonly prevalent in cancer populations and to incorporate a variant of a naturally occurring modulatory protein such as IL-2 as taught by ‘114; as part of the multimeric polypeptide of ‘392 in order to arrive at the instantly claimed invention. Since all the claimed elements were known in the prior art, and since one skilled in the art could have combined the elements as claimed by known methods with no change in the respective functions, the combination would have yielded predictable results before the effective filing date of the claimed invention.
Regarding claim 32, ‘392 teaches that in some cases, the recombinant polypeptide comprises a mutation in a human native B2M peptide sequence thereof and in the Heavy Chain sequence thereof so as to effect a disulfide bond between the B2M peptide sequence and Heavy Chain sequence (see pg. 3, para[0024). In some cases, the Heavy Chain sequence is an HLA and wherein the disulfide bond links one of the following pairs of residues: first linker position Gly 2, Heavy Chain (HLA) position Tyr 84; Light Chain (B2M) position Arg 12, HLA Ala236; and/or B2M residue Arg12, HLA residue Gly237 (see pg. 3, para[0024). Additionally, Figs. 9A-9F which depict the amino acid sequences of some embodiments, also indicate the mutation to a cys amino acid at position 84. Thus, ‘392’s teachings read on the claim limitations recited in instant claim 32, with respect to the cys-containing linkers that join the components of the claimed polypeptide.
Regarding claim 36, ‘392 also teaches that in some instances a multimeric polypeptide comprises two immunomodulatory polypeptides (e.g., two copies of the same immunomodulatory polypeptide) (see pg. 5, para[0036]); thereby corresponding to the claim limitations recited in instant claim 36.
In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the above claims would have been obvious to one of ordinary skill in the art within the meaning of 35 USC 103. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references discussed above.
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.
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Claims 21, 26, 31-32 and 36 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5 and 12 of Copending Application No. 18/234,640 (US Publication No. US20240067700A1) in view of WO2018/119114 A1 International Pub. Date: June 28, 2018 (cited in the IDS filed on 12/13/2024) (herein after “114”), as evidenced by GenCore Sequence Alignment instant SEQ ID NO: 241 v SEQ ID NO: 38, pp. 1 (herein after “GenCore”).
Copending Application No. 18/234,640, claim set filed on 02/20/2026, claims:
1. A single-chain T-cell modulatory polypeptide (TMP) comprising:
i) a KRAS peptide comprising a KRAS epitope expressed on a cancer cell, wherein the KRAS peptide has a length of from about 7 amino acids to about 16 amino acids, optionally from 8 amino acids to 12 amino acids;
ii) first major histocompatibility complex (MHC) polypeptide, wherein the first MHC polypeptide is a β2-microglobulin (β2M) polypeptide;
iii) a second MHC polypeptide, wherein the second MHC polypeptide is an MHC class I heavy chain polypeptide;
iv) one or more immunomodulatory polypeptides; and
v) an immunoglobulin (Ig) Fc polypeptide,
wherein the TMP comprises:
(a) at least one rigid peptide linker, optionally wherein the TMP comprises a rigid peptide linker between the Ig Fc polypeptide and one of the one or more immunomodulatory polypeptides; and/or
(b) at least one short flexible peptide linker comprising from 2-14 amino acids, optionally wherein the TMP comprises a short flexible peptide linker between the Ig Fc polypeptide and one of the one or more immunomodulatory polypeptides,
optionally wherein the TMP comprises one or more additional peptide linkers.
5. A TMP of claim 4, wherein:
(a) the β2M polypeptide and the MHC heavy chain polypeptide are joined by a disulfide bond that joins a Cys residue in the β2M polypeptide and a Cys residue in the MHC heavy chain polypeptide, optionally wherein a Cys at amino acid residue 12 of the β2M polypeptide is disulfide bonded to a Cys at amino acid residue 236 of the MHC heavy chain polypeptide;
(b) the β2-microglobulin polypeptide is joined to the peptide by a first linker comprising a Cys, and wherein a disulfide bond links a Cys present in the first linker with a Cys present in the MHC heavy chain polypeptide, optionally wherein the first linker comprises the sequence CGGGS(GGGGS)n (SEQ ID NO:220) or GCGGS(GGGGS)n (SEQ ID NO:217), where n is an integer from 1-10, e.g., 2 or 3, and a disulfide bond links the Cys in the linker with a Cys substituted for Tyr84 of the MHC heavy chain polypeptide; or
(c) the β2M polypeptide and the MHC heavy chain polypeptide are joined by a disulfide bond that joins a Cys residue in the β2M polypeptide and a Cys residue in the MHC heavy chain polypeptide, optionally wherein a Cys at amino acid residue 12 of the β2M polypeptide is disulfide bonded to a Cys at amino acid residue 236 of the MHC heavy chain polypeptide, and the β2-microglobulin polypeptide is joined to the peptide by a first linker comprising a Cys, and wherein a disulfide bond links a Cys present in the first linker with a Cys present in the MHC heavy chain polypeptide, optionally wherein the first linker comprises the sequence CGGGS(GGGGS)n (SEQ ID NO:220) or GCGGS(GGGGS)n (SEQ ID NO:217), where n is an integer from 1-10, e.g., 2 or 3, and a disulfide bond links the Cys in the linker with a Cys substituted for Tyr84 of the MHC heavy chain polypeptide (see Copending Application No. 18/234,640, claim 5).
12. A TMP of claim 1, comprising in order from N-terminus to C-terminus:
i) the KRAS peptide;
ii) optionally a peptide linker;
iii) the β2M polypeptide;
iv) optionally a peptide linker;
v) the MHC class I heavy chain polypeptide;
vi) optionally a peptide linker;
vii) an Ig Fc polypeptide;
viii) a rigid peptide linker or a short flexible peptide linker; and
ix) the one or more immunomodulatory polypeptides, optionally wherein when two or more immunomodulatory polypeptides are present, a peptide linker is interposed between each of the two or more immunomodulatory polypeptide; or
i) the KRAS peptide;
ii) a flexible peptide linker;
iii) the β2M polypeptide;
iv) a flexible peptide linker;
v) the MHC class I heavy chain polypeptide;
vi) a flexible peptide linker;
vii) the Ig Fc polypeptide;
viii) a rigid peptide linker or a short flexible peptide linker;
ix) a first copy of the at least one immunomodulatory polypeptide;
x) a peptide linker; and
xi) a second copy of the at least one immunomodulatory polypeptide, and
optionally wherein the peptide linker between the KRAS peptide and the β2M polypeptide comprises a cysteine; or
i) the KRAS peptide;
ii) a flexible peptide linker;
iii) the β2M polypeptide;
iv) a flexible peptide linker;
v) the MHC class I heavy chain polypeptide;
vi) a rigid peptide linker or a short flexible peptide linker;
vii) a first copy of the at least one immunomodulatory polypeptide;
viii) a rigid peptide linker or a short flexible peptide linker;
ix) a second copy of the at least one immunomodulatory polypeptide,
x) a peptide linker; and
xi) the Ig Fc polypeptide; and
optionally wherein the peptide linker between the KRAS peptide and the β2M polypeptide comprises a cysteine; or
i) the KRAS peptide;
ii) optionally a peptide linker;
iii) the β2M polypeptide;
iv) optionally a peptide linker;
v) the MHC class I heavy chain polypeptide;
vi) optionally a peptide linker;
vii) the one or more immunomodulatory polypeptides;
viii) the rigid peptide linker or a short flexible peptide linker; and
ix) an Ig Fc polypeptide, and optionally wherein the peptide linker between the KRAS peptide and the β2M polypeptide comprises a cysteine, and optionally wherein when two or more immunomodulatory polypeptides are present, a peptide linker is interposed between each of the two or more immunomodulatory polypeptide. (see Copending Application No. 18/234,640, claim 12).
However, Copending Application No. 18/234,640 does not claim wherein one or more variant IL-2 polypeptides, wherein the one or more variant IL-2 comprise the amino acid sequence set forth in SEQ ID NO:241.
‘114 teaches Figures 2B-2Q, which depict amino acid sequences of variant IL-2 polypeptides (see pg. 2, para [0006] and FIG. 2B-2Q). A sequence alignment of amino acid sequence corresponding to a variant IL-2 represented SEQ ID NO: 241 and ‘114’s SEQ ID NO: 38 depicted in Fig. 2B reveals a 98.5% identity (see GenCore, Sequence alignment). Thus ‘114 IL-2 variant reads on ii) one or more variant IL-2 polypeptides, as recited in instant claim 21. It would have been obvious to incorporate an IL-2 variant as part of the TMP claimed in Copending Application No. 18/234,640 because SEQ ID NO: 38 is a variant of a naturally occurring immunomodulatory protein (IL-2). The artisan of ordinary kill in the art would have been motivated to select a variant of IL-2 comprising the amino acid sequence set forth in SEQ ID NO: 241 with reasonable expectation of success because an IL-2 variant exhibits a reduced affinity for its counterpart costimulatory protein on the T cell (e.g., IL-2R) as compared to the affinity of the naturally occurring immunomodulatory protein for the counterpart costimulatory protein as taught by ‘114.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious over the claims of the above copending application in view of ‘114.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CLAUDIA E ESPINOSA whose telephone number is (703)756-4550. The examiner can normally be reached Monday-Friday 9:30-5:30 EST.
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/CLAUDIA ESPINOSA/ Patent Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654
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