DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s claim amendments received June 15, 2026 are acknowledged.
Claims 1-29, 32, and 44-49 have been canceled.
Claim 35 has been amended.
Claims 50-53 have been amended.
Claims 30, 31, 33-43, and 50-53 are pending in the instant application.
Applicant’s election without traverse of the invention of group I, and the species of the peptide antigen of SEQ ID NO:3, the TCR CDRs of SEQ ID NOs:10 (alpha chain) and 14 (beta chain), HLA-DP as an MHC restricting structure, no immune cell present (i.e. the “antigen binding molecule” must be soluble) and the disease acute myeloid leukemia (AML) in the reply filed on June 15, 2026 is acknowledged. In view of newly presented claim 50, the restriction requirement between inventions I and II as set forth in the 4/13/2026 restriction requirement has been withdrawn. Applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 37 and 38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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 June 15, 2026.
Claims 30, 31, 33-36, 38-43, and 50-53 are under examination in this office action.
Information Disclosure Statement
The IDS forms received 2/2/2024 and 6/15/2026 are acknowledged and the references cited therein have been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
Specifically, table 3 (beginning on page 79 of the substitute specification received 9/5/2024 discloses multiple polypeptide sequences in the absence of an accompanying SEQ ID number, which is against the rules. Note this same issue existed in the original specification filed 10/18/2023. Please note that if the sequences in the table are already part of eth sequence listing, all applicant needs to do is add the missing SEQ ID information into the table. IF there are sequences present in the table which are not presently part of the sequence listing, applicant will need to provide a new sequence listing in addition to that which is specified below.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, 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.
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.
Claims 30, 33, 35, 40, 42, 52, and 53 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exceptions, specifically mental processes, without significantly more. The claims recite methods for “selecting” an immunotherapeutic. The ways such reagents are recited as being “selected”, such as “identifying a peptide antigen that is encoded by a germline variation in an individual” is broad such that it encompasses everything from the method’s practitioner simply looking at data on a paper to obtaining a tissue sample and sequencing the individual’s genome. All other limitations in the independent as well as dependent claims are written is such a way that they encompass simply looking at data previously collected and then mentally “selecting” something such that an outside observed would be unable to say with certainty if the present claimed method is or is not being practiced. Note this is in contrast to newly presented claims 50 and 51 (which are not part of this rejection) which require the practitioner of the claimed method to perform an active, observable practice step including administering the selected agent to the patient (claim 50) or activating donor T cells with a peptide antigen (claim 51). It should be pointed out that applicant has recited pseudo-parallel claims that recite the same limitations as the instant claims but comprise an observable active step of administration (compare for example independent claims 30 and 31) such that integrates the mental observations presently recited for example as “selecting” and “identifying”, into something more than the act of observation itself. Thus judicial exception is not integrated into a practical application because as presently recite the practitioner of the claimed method is not actually required to do anything that an outside observed could see and thereby know that the claimed method was being practiced. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because they are not integrated into a practical, observable endpoint, unlike claim 50 which requires administration of the selected immunotherapeutic to the patient. Amendment of the claims to recite observable, physical method steps is the most obvious way to obviate the instant rejection.
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 30, 31, 33-36, 38-43, and 50-53 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Applicant has broadly claimed methods wherein immunotherapeutic agents comprising an antigen binding domain that has the ability to bind the peptide expressed by an allelic polymorphism present in the individual are used to treat a disease (see particularly independent claims 30 and 31). Alternatively, the claims encompass active vaccination with the peptide identified form an allelic polymorphism in the hope of eliciting an immune response directed against the polymorphic peptide (claim 31). Notably the allelic peptide is recited as being capable of binding to and being presented by an MHC molecule (claim I and class II restriction are both recited, see for example claims 33 and 34) while the “immunotherapeutic agent” is recited as comprising a dizzying array of structurally distinct “antigen binding molecules” loosely orbiting either TCR or BCR (i.e. antibodies which are soluble BCRs) based ligand binding patterns, wherein such antigen binding molecules can be components of a cell (such as a CAR or transgenic TCR cell line). To support such breadth, applicant discloses examining potential genetic polymorphisms between host and graft materials as part of allo-HSCT cancer therapy and single cell cloning T cell receptors that recognize such polymorphisms from patients (see example 1 in particular). Data concerning the administration of such TCR, either as expressed on a T cell as a conventional TCR transgene or a soluble molecule, appear to be disclosed.
The number of potential “antigen binding domains” encompassed by claimed invention is enormous, as the broadest claims fail to identify either polymorphic peptide antigen or the molecule binding said antigen. Dependent claims recite that the “antigen binding molecule” can be based on the structure of either TCR or BCR, and while both are assembled combinatorially using V(D)J recombination, the ways in which antibodies and T cells recognize antigen are distinct, even if B cell antigens are limited to comprise peptide-MHC complexes (“TCR-like” (TCRL) antibodies, see Li et al. particularly the right column of the introduction).
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway et al., see entire selection). TCRs are broadly similar, and although TCR typically undergo less somatic hypermutation as compared to BCR since binding to the MHC restricting element as well as the antigenic peptide is required, all six CDRs contribute to binding either the MHC or the presented peptide. It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al., see entire document, particularly the abstract and the middle of the left column of page 1982 as well as Winkler et al.) with single point CDR mutations in TCR also demonstrating loss of antigen binding (Goyarts et al., see entire document). Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within a BCR or TCR which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
Artisans are well aware that knowledge of a given antigen (for instance human PADI4) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document). Similarly, Lloyd et al. teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding, as their sequencing studies revealed that out of 841 unselected and 5,044 selected antibodies, all but one of the 49 functional VH gene segments was observed (see entire document). Goel et al. disclose the synthesis of three mAbs that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (see entire document). Further, it should be noted that degenerate binding of the same structural motif by antibodies does not require the existence of sequence homology or identity at any of their CDRs or other chemical similarities at the antigen-binding sites; side chain mobility of epitope residues can confer steric and electrostatic complementarity to differently shaped combining sites, allowing functional mimicry to occur (Lescar et al., see entire document, in particular Abstract and Discussion). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequence bound in a population of antibodies that bind to a given antigen, no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen. Indeed, Kanyavuz et al. teach that “Theoretically, under physiological conditions, the human immune system can generate BCRs with 1026 distinct sequences, an astronomical number that is far greater than the calculated number of all B cell clones that can be generated during the lifespan of a healthy human (estimated to be 4 × 1014).
It should be noted that claims 40 and 41 recite various peptides, but as discussed above the sequence/structure of the ligand does not provide artisans with knowledge for how to make a receptor that necessarily binds that structure, as a very large number of structures are theoretically possible. In claims 42 and 43, applicant provides partial structures by way of SEQ ID number. It should be noted that based upon the specification these sequence appear to have been recovered from patient TCR, but the chain of dependency does not specify that the recited CDRs are for a T cell receptor rather than a B cell receptor. Applicant has provided no data or working example wherein TCR CDR sequences can be put into antibody frameworks to make a functioning antigen binding domain (or vice versa) and based upon the structural knowledge of how antigen binding (geometry, orientation, etc.) differs when comparing BCR and TCR artisans would very reasonably expect no binding activity at all if CDRs are put into the “wrong” framework sequences. Further, the recited sequences in part (I) of claims 42 and 43 are insufficient because as discussed above all six CDR are reasonably needed, and if no specific sequence is required the claim reads upon the incorporation of random sequence. Given that mutations as small as a single CDR residue in both BCR and TCR can abrogate binding as discussed above, artisans would not reasonably be able to make such antigen binding molecules that still actually bind antigen in the absence of undue experimentation. Parts (II) and (III) of claims 42 and 43 recite either 6 fully defined CDRs (part II) or a complete alpha and beta TCR chain (part III) but as presently recited such elements are randomly assorted. This is a problem as the TCR sequence do not bind the same peptide-MHC complexes, and thus mixing elements from a TCR binding “A” with elements from one binding “B” most reasonably will yield a TCR that binds nothing.
Claim 52 recites that the antigen binding molecule comprises polypeptide sequences at least 80% identical to SEQ ID NOs:10 and 14, which are the alpha and beta TCR chains sequences from clone 2 in working example 1. The claim as written allows for sequence variation anywhere, including within the CDRs, and given the correlation between CDR sequence and binding activity as discussed at length above, artisans could not make working molecules in the absence of extensive trial and error experimentation. Further, it should be noted that applicant elected a soluble TCR, and while higher avidity TCR formats (such as tetramers) are well known, such an election encompasses as its most easily envisioned member a complex of SEQ ID NO:10 and SEQ ID NO:14. Note that such a complex only has a single antigen binding site, and given the lower affinity of TCR for peptide as compared to antibody-antigen interactions and the lack of avidity effects (such as present when a T cell expresses numerous copies of the TCR in question) it is difficult to see what therapeutic use such a reagent possibly could have, especially as the individual in question is not ever recited as actually even comprising the peptide-MHC needed to serve as the ligand for the soluble receptor. It should be apparent that if the patient/individual does not express the ligand there seems to be no point in administering the receptor no matter what the receptor actually is with regard to its structure.
Therefore, in view of the breadth of the claims, the teachings of the prior art and the guidance and direction of the instant specification, artisans would be unable to make and use the full breadth of what has been presently claimed without first conducting additional unpredictable undue basic science research and experimentation.
Claims 35, 36, and 40-43 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claims 35 and 36 are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: Specifically, the “antigen binding molecule” is recited as being chosen from among structurally unrelated elements, such as T cell receptors and antibodies (a soluble version of the B cell receptor) as well as being completely generic in structure (structurally an antigen is simply a ligand which is bound by its antigen binding domain which is a receptor). It should be noted that generally chimeric antigen receptors comprise the antigen binding domain of an antibody and the signaling component of a T cell receptor, and thus the actual part of a CAR that binds antigen (i.e. the “antigen binding domain” portion) is overwhelmingly an antibody in the art and the specification discloses no working example wherein applicant generated a CAR.
The Markush grouping of claims 40 and 41 are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: Specifically, the recited SEQ ID numbers encode peptides from structurally unrelated antigens. As such they do not share a common structure and are non-interchangeable in the instant methods as such peptide antigens depend upon the genotype of the treated individual as per the independent claims, and note that the independent claim does not specify any genotype. Thus they are clearly not functional equivalent from the standpoint of the individual in question as set forth in the claimed invention.
The Markush grouping of claims 42 and 43 are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: Claims 42 and 43 recite that the “antigen binding molecule” of the independent claim comprises either CDR3 sequences alone or in combination with CDRs 1 and 2, or full length sequences that happen to be TCR alpha and beta chains this are specific for particular peptide-MHC ligands. These structures are recited as being mixed and matched even though in order to reasonably bind the correct ligand such elements cannot be randomly assorted. Thus the sources of the sequence, and the ligands to which they bind are structurally distinct and as such the recited SEQ ID numbers (which are also structurally distinct as evidence by the need for so many SEQ ID numbers to capture their sequence diversity) have unique functional properties and are not reasonably substitutable one for another.
To overcome these rejections, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 30, 31, 33-36, 39, 50, and 51 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dossa et al. (of record as NPL citation 4 on the 2/2/2024 IDS).
Dossa et al. disclose administration of T cells transduced with a cloned T cell receptor that recognizes the minor histocompatibility peptide antigen HA-1 (which has a single amino acid polymorphism as compared to the normal sequence) in the context of common HLA-A allele , in order to promote a graft versus leukemia effect following relapse of AML patients treated by allo-HSCT (see entire document, particularly the title, abstract, introduction and discussion sections). It is disclosed that HA-1 is highly expressed on leukemia and hematopoietic cells but not well expressed elsewhere (see particularly the introduction and discussion). Administration of T cells expressing the TCRs cloned by Dossa et al. allows for recognition of the HA-1 peptide expressed in the leukemia cells while sparing other cell types as they do not express the antigen at levels high enough to be readily detected by the immune system, thus minimizing the potential for graft versus host disease.
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Michael Szperka whose telephone number is (571)272-2934. The examiner can normally be reached Monday-Friday 8:30-5:00.
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, Misook Yu can be reached at 571-272-0839. 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.
Michael Szperka
Primary Examiner
Art Unit 1641
/MICHAEL SZPERKA/ Primary Examiner, Art Unit 1641
Prosecution Insights