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
This application is a U.S. national phase of International Application No. PCT/DK2021/050188, filed on 06/14/2021, which claims domestic benefit to US provision application 63/040,220, filed 06/17/2020.
Claim Status
The Amendment, filed on 06/20/2023, is acknowledged in which:
Claims 1-116 are canceled.
Claims 117-134 are new.
Claims 117-134 are pending in the instant application and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/11/2025 has been considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement (pg 33-34). 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The following guidelines illustrate the preferred layout for the specification of a utility application. These guidelines are suggested for the applicant’s use.
Arrangement of the Specification
As provided in 37 CFR 1.77(b), the specification of a utility application should include the following sections in order. Each of the lettered items should appear in upper case, without underlining or bold type, as a section heading. If no text follows the section heading, the phrase “Not Applicable” should follow the section heading:
(a) TITLE OF THE INVENTION.
(b) CROSS-REFERENCE TO RELATED APPLICATIONS.
(c) STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT.
(d) THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT.
(e) INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A READ-ONLY OPTICAL DISC, AS A TEXT FILE OR AN XML FILE VIA THE PATENT ELECTRONIC SYSTEM.
(f) STATEMENT REGARDING PRIOR DISCLOSURES BY THE INVENTOR OR A JOINT INVENTOR.
(g) BACKGROUND OF THE INVENTION.
(1) Field of the Invention.
(2) Description of Related Art including information disclosed under 37 CFR 1.97 and 1.98.
(h) BRIEF SUMMARY OF THE INVENTION.
(i) BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S).
(j) DETAILED DESCRIPTION OF THE INVENTION.
(k) CLAIM OR CLAIMS (commencing on a separate sheet).
(l) ABSTRACT OF THE DISCLOSURE (commencing on a separate sheet).
(m) SEQUENCE LISTING. (See MPEP § 2422.03 and 37 CFR 1.821 - 1.825). A “Sequence Listing” is required on paper if the application discloses a nucleotide or amino acid sequence as defined in 37 CFR 1.821(a) and if the required “Sequence Listing” is not submitted as an electronic document either on read-only optical disc or as a text file via the patent electronic system.
The disclosure is objected to because of the following informalities:
“aming” should read “among” (pg 10, line 16)
“sFv” should read “scFv” based on subsequent use (pg 21, line 21)
“bsAb” should be capitalized base on subsequent use (pg 22, line 2)
“potein A” should read “Protein A” (pge 29, line 12)
Appropriate correction is required.
The use of the terms “Biovia Discovery Studio” (pg 28, line 7) and “expiCHO” (pg 31, line 20), which are trade names or marks used in commerce, has been noted in this application. Each term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (pg 34, lines 11, 14-15, 18, 21, 24-25, and 28). 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.
Claim Objections
Claim 130 is objected to because of the following informalities: “Error! Reference source not found” (line 4). Appropriate correction is required.
Improper Markush Rejection
Claim 134 is rejected on the basis that it contains 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 autoimmune diseases is 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: “type 2 diabetes,” “allergy,” and “graft-versus-host disease” as recited in the claim are not clinically considered autoimmune diseases (Global Autoimmune Institute, 2024).
To overcome this rejection, 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 § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 126 and 129 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.
As currently written the “or” conjunction introduces ambiguity to the claim. It is unclear if “an isolated nucleic acid molecule” as recited in claim 126 or “a pharmaceutical composition” in claim 129 are meant as preambles to modify the remaining details within the claims. Examiner recommends rewriting the claims to either clearly define the preamble and its application to subsequent limitations (i.e. “An isolated nucleic acid molecule encoding (a)… or (b)…” or “A pharmaceutical composition comprising (a)… or (b)…) or drafting separate the claims for the individual embodiments (i.e. (1) an isolated nucleic acid molecule encoding the antibody of claim 117 and (2) an isolated nucleic acid molecule encoding the SADA polypeptide of claim 121).
Claim Rejections - 35 USC § 112(a)
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.
Claim 122 is 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.
The instant claim is drawn to a SADA polypeptide conjugated to bispecific antibody, wherein the antigen binding fragment according to claim 117 is linked to a second scFv capable of binding DOTA and/or DTPA. The instant claim contains functional language by claiming a genus of antibodies by what they do (function), rather than by what they are (structure). MPEP 2173.05(g) teaches that "Unlimited functional claim limitations that extend to all means or methods of resolving a problem may not be adequately supported by the written description or may not be commensurate in scope with the enabling disclosure, both of which are required by 35 U.S.C. 112(a) and pre-AIA 35 U.S.C. 112, first paragraph. In re Hyatt, 708 F.2d 712, 714, 218 USPQ 195, 197 (Fed. Cir. 1983); Ariad, 598 F.3d at 1340, 94 USPQ2d at 1167. For instance, a single means claim covering every conceivable means for achieving the stated result was held to be invalid under 35 U.S.C.112, first paragraph because the court recognized that the specification, which disclosed only those means known to the inventor, was not commensurate in scope with the claim. Hyatt, 708 F.2d at 714-715, 218 USPQ at 197." In this case, the antibodies claimed are based on the epitope to which they bind, not the structure of the antibody that would result in the claimed epitope binding. The instant disclosure does not demonstrate an adequate number of species of the claimed genus nor does it adequately describe the structure required to achieve the claimed function in such a way as to demonstrate to a skilled artisan that applicant was in possession of the genus as claimed at the time of filing.
The instant disclosure discloses SADA polypeptide fusions (e.g. SEQ ID NOs: 26-30) comprising an scFv against DOTA based on humanized C825 (SEQ ID NO:45), but does not describe the structure that would be required for an ordinarily skilled artisan to envision all antibodies would bind to the same epitope as those claimed and/or additional epitope DTPA. Furthermore, the state of the art even several years after the effective filing date of the claimed invention demonstrates that the prediction of epitope binding based on antibody structure was still not fully understood.
For example, Hummer (Current Opinion in Structural Biology 74(102379);1-7) teaches that traditional methods for antibody development, such as deriving antibodies from hybridomas of inoculated animals or from library assembly followed by display techniques are not only costly and time consuming but also are not necessarily able to produce antibodies that bind to the desired site (epitope) on an antigen. Hummer teaches that computational antibody design methods offer a way to overcome these limitations, but are held back by the lack of accurate antibody and antigen structures (page 1, right column, ¶ 2). Hummer provides a review on how advances in protein structure prediction and other areas are bringing us closer to being able to entirely computationally designed antibodies that bind strongly to a defined epitope (page 1, right column, ¶ 3) demonstrating that in 2022 predictable structure function relationships were still not known. Hummer acknowledges this in their discussion of future directions stating:
“Several challenges still remain for true computational structure-based antibody design. While there has been great progress in protein structure prediction, current methods are not yet able to accurately predict the position of the side chain atoms or structural changes on binding. For antibodies, accurately modeling the CDR-H3 loop remains a major obstacle. Additionally, improvements in paratope and epitope prediction, both in terms of accuracy and specificity (predicting the types of binding interactions for residues), will be needed to help improve docking for high-throughput virtual screening.” (page 4, right column, ¶ 3).
In summary, Hummer teaches the difficulties in predicting the relationship between antibody structure and the epitopes to which they bind demonstrating a lack of predictability in the field between antibody structure and function.
Overall, it is not evident by the disclosure, or the prior art, that applicant was in possession of an adequate number of species of antibodies which bind to the same epitope as the antibodies of the instant claims. Furthermore, as discussed above, there is no disclosed or art recognized correlation between structure and function which would allow for the predictable generation of antibodies that bind to DOTA and/or DTPA. Therefore, instant claim 122, as currently written, was determined not to meet the written description requirement of 35 USC 112(a).
Claim 131 is 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 specification, while being enabling for “treating”, “alleviating” and/or “diagnosing symptoms” in a medical condition (drawn to include cancer according to claims 132 and 133) in a subject characterized by CD38 expression, does not reasonably provide enablement for “preventing” said medical condition. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Regarding the prevention of cancer, the America Cancer Society maintains that “There's no sure way to prevent cancer, but you can help reduce your risk by making healthy choices like eating right, staying active, and not smoking” (Cancer risk and prevention. American Cancer Society. Accessed January 22, 2025. https://www.cancer.org/cancer/risk-prevention.html. Internet – Wayback Machine). And, while anti-CD38 antibodies have been suggesting for use in cancer treatment and diagnosis (US 11,414,496 B2), there is no evidence in the prior art that utilizing anti-CD38-SADA polypeptides disclosed enable cancer prevention without undue experimentation. See MPEP § 2146.01.
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 117-119, 126-130 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ellis (J Immunol. 1995;155(2):925-937; IDS cited).
Ellis teaches a humanized CD38 antibody comprising the instantly claimed CDRs with nucleic acid and amino acid sequences for humanized Ab VH/VL sequences sharing 92.4% and 95.3% identity to instant SEQ ID NOs: 16 and 6, respectively (H3S aka humanized IgG1; murine residues at VH residues 67-73, 28, 29, and 78 as disclosed in Figure 3 and Table 1; see alignments below - CDRs highlighted). Ellis teaches methods of expressing humanized antibodies using cloning vectors transfected into NS0 or CHO cells and purifying Ab from culture medium (pg 927 - “Expression of humanized antibodies”). Ellis further teaches this antibody induces Ab-dependent cellular toxicity against CD38-positive cell lines (Figure 7-9) and thus proposes said Ab as useful for treating multiple myeloma (MM) and other diseases involving CD38-positive cells.
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Claims 117-120, 126-130 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 11,414,496 B2 (herein Elias; priority date Jan 23, 2019).
Elias teaches an scFv CD38 binding protein CD38TR1 with identical CDRs and with 96.3% and 94.7% identity to claimed VH/VL sequences (SEQ ID NOs: 26 and 27, respectively; FIG 6E; alignments shown below with CDRs highlighted). Elias teaches that isolated antibodies disclosed are ordinarily prepared by recombinant nucleic acid techniques (expression vector for transformation into host cells) wherein the antibody is recovered from a cell or cell culture from which it was expressed (column 26-27 spanning ¶). Elias further teaches pharmaceutical compositions comprising anti-CD38 binding antibodies for use in treating or diagnosing (e.g. labeling with radioactive isotopes; column 29, ¶ 4) diseases which overexpress CD38 (Abstract; columns 27-30).
Instant SEQ ID NO:6 (Qy) aligned with Elias SEQ ID NO:27 (Db)
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Instant SEQ ID NO:16 (Qy) aligned with Elias SEQ ID NO:26 (Db)
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Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 121-123, 126-129, and 131-133 are rejected under 35 U.S.C. 103 as being unpatentable over Elias as applied to claim 117 above, and further in view of US 11,583,588 B2 (herein Santich).
Regarding claims 121-122, 126-128 and 131-133, Elias teaches claim 117 as discussed above. Elias further teaches CD38 is upregulated in many hematopoietic malignancies (e.g. MM) and is used as a prognostic marker in leukemia (column 1, lines 55-64).
Elias does not teach linking a CD38 antibody to a self-assembly disassembly (SADA) polypeptide.
Santich teaches SADA nucleotides and polypeptides derived from tetramerization domains of p53, p63, p73, hnRNPC, SNAP-23, Stefin B, KCNQ4, or CBFA2T1 (SEQ ID NOs: 1-16) and conjugates thereof (Figure 2). Santich teaches a SADA can be covalently attached to a binding domain (e.g. antibodies) for effective delivery of a payload (e.g. radioactive isotope; column 4, line 62) to a target site (column 41, ¶ 3). Santich teaches a conjugate comprising bispecific antibody comprising a first scFv that binds a tumor target and a second scFv that binds a DOTA moiety comprising a radioactive payload (claim 1), wherein the payload is a therapeutic or diagnostic radioactive payload (claim 4). Santich explicitly teaches an exemplary SADA-bispecific DOTA-engaging (SADA-BiDE) conjugate wherein the tumor target is anti-GD2 (Example 1) or HER2 (Example 12) and teaches constructs were cloned into standard IgG expression vectors using common molecular cloning techniques for expression in either CHO-S, expiCHO or expiHEK suspension lines after which supernatants were collected and constructs were purified therefrom (column 103, lines 38-56). Santich teaches the SADA conjugates disclosed can be used in pharmaceutical compositions (column 45, lines 50-67) and further teaches in vivo efficacy of p53 SADA-BiDE in reducing tumor burden (Example 7; Figure 8B).
A skilled artisan would recognize that the tumor target in a SADA conjugate as taught by Santich can be tailored depending on the tumor expression profile. Elias teaches that CD38 is expressed on hematopoietic malignancies including MM. Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that the tumor targeting domain in the SADA conjugate as taught by Santich could be modified for the CD38 targeting domain as taught by Elias as a means to tailor the SADA molecule and corresponding payload within a pharmaceutical composition designed to target and treat hematopoietic malignancies within scope of the instant claims.
Regarding claim 123, the combined teachings of Elias and Santich teach claim 122 as discussed above.
Santich further teaches a sequences for the HER2-SADA-BiDE that are within 86% identity to instant SEQ ID NO: 28 (SEQ ID NO:67), 85.4% identity to instant SEQ ID NO: 29 (SEQ ID NO:65), and 87.8% identity to instant SEQ ID NO: 30 (SEQ ID NO:31) differing in only the amino acids (AA) corresponding to the VH and VL sequences of the HER2 scFv (i.e. remaining domains share 100% identity with AA corresponding to “(G4S)4-huC825 anti DOTA scFv-linker-P53-linker-His tag” within instant sequences; see example annotated alignment below).
Instant SEQ ID NO:28 (Qy) aligned with Santich SEQ ID NO:67 (Db)
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It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that substituting the VH/VL sequences for the anti-CD38 scFv as taught by Elias for the HER2 scFv domain within the SADA polypeptide as taught by Santich would predictably generate an amino acid sequence of a SADA polypeptide with CD38 binding within the allowed variance of SEQ ID NOs: 28-30 of the recited claim (e.g. utilizing Elias SEQ ID NOs: 26 and 27, which collectively comprise 14 residues different from instant SEQ ID NOs:16 and 6, a skilled artisan could reasonably generate a SADA-CD38 scFv conjugate with up to 97.6% identity to the instantly claimed sequences).
Allowable Subject Matter
Sequences with 100% identity to SEQ ID NOs: 6, 16, and 28-30 are free from prior art.
Claims 124 and 125 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNAH SUNSHINE whose telephone number is (571)270-7417. The examiner can normally be reached M-Th & Second Friday 8:30am-5pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached at (571) 272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647