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 .
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 5/6/2026 has been entered.
Status of the Claims
2. Claims 1-47 are the original claims filed 9/8/2022. In the Preliminary Amendment of 9/8/2022, claims 2, 4-5, 7, 10, 13, 16, 19, 22-23, 25-26, 28, 33-34, 37, 39-40, 42 and 45-47 are amended and claims 3, 6, 8-9, 11-12, 14-15, 17-18, 20-21, 24, 27, 29-32, 35-36, and 43-44 are cancelled. In the Response of 12/2/2025, Claims 1, 5, 22, 26, 28, 33, 37, 38, 40, 42 and 45-47 are amended, and Claims 2, 4, 7, 10, 13, 16 and 19 are canceled. In the Response of 5/6/2026, Claims 1, 5, 22-23, 25-26, 28, 33-34, 37-38, 40-42 and 45-47 are amended and new Claims 48-50 are added.
3. Claim 40 is improperly amended in the claim set of 5/6/2026 to the extent it does not reflect corresponding claim 40 in the claim set of 12/2/2025.
Claim 40 (12/2/2025):
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Claim 40 (5/6/2026):
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Applicants failed to include the comma much less its deletion in the claim set of 5/6/2026. In the interest of compact prosecution, rather than mailing a Notice of Non-Compliant Amendment, Claim 40 in the claim set of 5/6/2026, is amended by Examiner’s Amendment to rectify the deficiency.
4. Claims 1, 5, 22-23, 25-26, 28, 33-34, 37-42, and 45-50 are pending.
The amendments to the claims raise new grounds for objection and rejection.
Priority
5. USAN 17/910,327, filed 09/08/2022, and having 1 RCE-type filing therein, is a National Stage entry of PCT/EP2021/ 056349, International Filing Date: 03/12/2021, claims foreign priority to EP 20163019.1, filed 03/13/2020.
Information Disclosure Statement
6. As of 5/26/2026, a total of five (5) IDS are filed: 9/8/2022; 12/12/2022; 3/3/2025; 12/2/2025; and 2/10/2026. The corresponding initialed and dated 1449 form is considered and of record. The submissions are in compliance with the provisions of 37 CFR 1.97.
Withdrawal of Objections
Claim Objections
7. The objection to Claim 38 because of informalities is withdrawn.
Claim 38 is amended to delete “an natural killer T cell.”
Claim Objections
8. The objections to Claims 22 and 47 because of informalities is withdrawn.
a) Claim 22 is amended to delete “antibody or derivative thereof”.
b) Claim 47 is amended to replace the phrase “comprising contacting a sample the cancer” with “comprising contacting a sample comprising cells from the cancer”
Withdrawal of Rejections
Claim Rejections - 35 USC § 112(b)
9. The rejection of Claim 38 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn.
Claim 38 is amended to replace a “g/d T cell” with “a γ/δ T cell.”
Claim Rejections - 35 USC § 112(b)
10. The rejection of Claims 28, 37-42, and 45-46 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite are withdrawn.
a) Claim 28 is amended to recite the structure for the polypeptide as being one of elements (a)-(d).
b) Claim 37 (and claims 38-39) is amended to clarify that the immune cell comprises the polypeptide of claim 1 or nucleic acid encoding the same, and what the polypeptide is comprised of.
c) Claim 40 is amended by Examiner’s Amendment to insert the deletion of the comma as explained under section 3 herein above.
Claim Rejections - 35 USC § 112(d)
11. The rejection of Claim 47 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 is withdrawn.
Claim 47 is amended to recite that the immune cell targets human ROR2.
Claim Rejections - 35 USC § 112(a)
Written Description
12. The rejection of Claims 1-2, 4-5, 7, 10, 13, 16, 19, 22-23, 25-26, 28, 33-34, 37-42, and 45 and 46-47 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 is withdrawn.
The claims are amended to delete “antibody or derivative thereof” throughout the claim set.
Rejections Maintained
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.
Written Description/ New Matter
13. The rejection of Claim 47 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 is
maintained.
Applicants Claim 47 is allege amended to address this rejection.
Response to Arguments
Claim 47: A method for determining the susceptibility of a cancer to therapy by a recombinant immune cell that targets human ROR2, comprising contacting a sample comprising cells from the cancer with polypeptide of claim 1 and identifying the cancer as a ROR2-positive cancer.
The term “susceptibility” is used twice in the specification, and without a definition, the Office relies on a standard dictionary definition: www.merriam-webster.com/ dictionary/susceptibility: the quality or state of being susceptible especially; lack of ability to resist some extraneous agent (such as a pathogen or drug): sensitivity.
The specification does not disclose whether the contacting step of the method with an immune cell comprising the polypeptide of claim 1 with a cell sample is sufficient to assess in the absence of detailed bioassays as reasonable support to conclude that the identification of the cell being ROR2-positive renders the cell susceptible to immune therapy. The detection of the biomarker on a cell sample is not demonstrated to correlate with the cell-based expression of ROR2 whether the corresponding cancer has the ability to resist the immune cell or is sensitive to the immune cell, i.e., that is susceptible to the immune cell. The Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., lnc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
The rejection is maintained.
Enablement
14. The rejection of Claim 46 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 is maintained.
Applicants allege Claim 46 is amended to address this rejection.
Claim construction
Claim 46: A method of treatment comprising administering the pharmaceutical composition of claim 40 to a cancer patient that has a ROR2-positive cancer.
Response to Arguments
The amendment to recite “a cancer patient that has a ROR2-positive cancer” clarifies that the method is therapeutic for an ROR2 expressing cancer in the subject. However, the response is incomplete.
The amendment of claims 1, 40 and 42 in the Response of 5/6/2026 does not overcome the outstanding grounds for rejection. Applicants have not addressed the original grounds for rejection, namely, the breadth and scope of the ROR2 cancer and the breadth and scope of the ingredients in the pharmaceutical composition comprising the polypeptide of claim 1, a nucleic acid encoding the polypeptide, or a cell comprising the polypeptide or nucleic acid. Notably as to claim 1 for the HCCDR1-3 combinations, each of the pharmaceutical ingredients encompass the same combinations. That claim 40 depends on claim 1 thereby encompasses both the antibody VH/VL CDR1-3 and that are required to be therapeutic against any ROR2 cancer in any patient having the cancer.
A nucleic acid encoding the polypeptide reads on gene therapy.
A cell comprising the nucleic acid reads on gene therapy.
Disclosure in the Specification
[0227] Clones hX3.12.5 and hX3.12.6 also bound to breast cancer cell line T47D (ROR2+, ROR1−) and renal cell adenocarcinoma cell line 786-O (ROR2+, ROR1+) but not to breast cancer cell line MDA231 (ROR2−, ROR1+) (FIG. 13A).
The specification does not support the genus of any cancers in any patient being treated with the one or all of the reagents of claim 40. The specification does not support treatment of any cancer using any polypeptide of claim 1, any nucleic acid encoding the polypeptide of claim 1, any CAR that reads on gene therapy and/or any cell comprising the nucleic acid reads on gene therapy.
The scope of the claims must bear a reasonable correlation with the scope of enablement. See In re Fisher, 166 USPQ 19, 24 (CCPA 1970). "[T]o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.'" Genentech, Inc. v. Novo Nordisk, A/S, 108 F.3d 1361, 1365 (Fed. Cir. 1997) (quoting In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993)).
Prior Art Status: Immunotherapeutics especially cancer therapy is unpredictable
Four (4) art references spanning nearly 20 years in the field of immunotherapeutics recognize the complexity of antibody delivery to tumors in vivo are Fujimori et al. (J. Nuc. Med. 31:1191-1198 (1990)); Beckman et al. (Can. 109:170-179 (2007)); Thurber et al. (Adv. Drug Deliv. Rev. 60:1421-1434 (2008)); and Rudnick et al. (Can. Biotherp. & Radiopharm. 24: 155-162 (2009)).
Fujimori teaches for further understanding of Mab distribution in the tumor, one must consider as well the microscopic pharmacology: transport across the capillary wall, transport in tumor interstitium, cellular binding and metabolism. Fujimori discusses predictive models for accessing tumor antigen availability by Mab to examine the relationship between affinity and distribution. Fujimori teaches on p. 1196, Col. 2, ¶1:
“One strategy to overcome the binding-site barrier would be to increase the initial Mab dose. Even though Mab concentration in tumor does not always increase linearly as initial Mab concentration increases, a high initial plasma concentration leads to better percolation and results in more uniform distribution in tumor. Increasing Mab dose, however, decreases the specificity ratio and may cause toxicity or other side effects. For each Mab species and set of circumstances, there is an inherent balance of factors. Other causes of heterogeneous distribution include the functional and anatomical heterogeneity of tumors and their vessels..., and the elevated interstitial tissues…”
Beckman teaches on p. 175, Col. 2, ¶2-4:
“Optimizing biodistribution properties of Ab constructs depends on a large number of host and tumor variables. These include: the density and distribution of target Ag in tumors and normal tissues: the degree of target occupancy and residence tiemr equired for tumor cell kill; possible toxicities from normal tissue distribution; tumor size and vascularity; tumor interstitial pressure, convection and diffusion; and metabolism and internilzation rates for Ab-Ag constructs.
An equally large number of Ab construct and therapy variables are available for optimization, including size, charge, and valence; constant region type and glycosylation pattern; presence or absence of a radioisotope or a toxic moiety; dose, route, and schedule of administration; and use of a traditional or a pretargeting strategy. Given the complexity of the problem, systematic preclinical programs may enhance the likelihood of success in subsequent clinical studies. Such preclinical investigations should integrate both experimental and theoretical approaches.
Preclinical studies of a putative Ab-based therapeutic agent can encompass a variety of constructs, differing in molecular weight, affinity, valence, and/or other features of interest, which bind to the same epitope as demonstrated by competition experiments. The Ag density and target affinities should be known for both tumor cells and cross-reacting normal tissues, and the percent target occupancy and required residence time for tumor cell kill should ideally be investigated in vitro. Similarly, rate constants for Ab-Ag internalization should be determined, if applicable. Dose and schedule should be varied and antitumor efficacy, pharmacokinetics, overall biodistribution, homogeneity of intratumoral distribution, and tumor microvessel density and distribution ideally should be measured in tumor-bearing animals with a variety of tumor sizes.”
Studies in tumor-bearing rodents are often confounded by lack of normal tissue reactivity with Ab constructs directed toward human Ags, but studies in transgenic animal can be performed in some instances to alleviate this issue.”
Thurber teaches on p. 1431, Col 2, ¶3:
“Analyzing the fundamental rates that determine antibody uptake and distribution provides a theoretical framework for understanding and interpreting targeting experiments and improving on the limitations of uptake. It also provides a background for a more rational design of in vitro experiments, animal studies, and clinical trials. The insight gained from this type of modeling has multiple implications for imaging and therapy. For example, not all cells are exposed to the “average” concentration obtained in a tumor. A significant portion of cells can survive even if the tumor-averaged concentration is well above the LD50 in vitro. Also, the concentration that cells in a solid tumor are exposed to ([Ab]surf) is well below the plasma concentration. This means that the bulk antibody concentration in an in vitro spheroid experiment is not analogous to the plasma concentration but is actually well below it; large doses are required to overcome this poor extravasation. Knowing the rate of uptake in a tumor and clearance from the plasma and normal tissues also provides estimates of ratios between tumor and normal tissue concentrations, and these ratios are important in both imaging and therapy. These examples illustrate the utility of combining theoretical analysis also suggest ways to rationally improve uptake, and determining the limiting rates is the first step in overcoming these problems.”
Rudnick teaches on p. 155, Col. 2:
“Not strictly limited to tumor cells, target antigen is commonly expressed on normal tissue, found in circulation, and shed into the tumor interstitial space. These nontarget pools of antigens can reduce treatment effectiveness, increase systemic clearance, and increase side-effects (especially for radioimmunoconjugates) by impairing mAb specificity for the tumor.”
and on p. 158, Col. 2, last ¶ - p. 159, Col. 1:
“…antigen selection will be a critical factor for internalization and catabolism of mAbs. The relative rates of antigen recycling and dissociation are important in mAb penetration into tumors. Therefore, in applications dependent on targeting every cell of a tumor, the mAb needs to dissociate before it is internalized and degraded. In the case of ADCC, a slow internalizing antigen would be the best target. However, if one is trying to deliver a cytotoxic agent to the cytoplasm of cells in a limited region of a tumor, such as the vasculature, a mAb with slow dissociation targeting a rapidly recycling antigen would be appropriate. These are just simple examples of the interplay of affinity, avidity, and efficacy in tumor targeting.”
Therefore, due to the unpredictability of immunotherapeutics in general and in view of the insufficient guidance and/or working examples concerning the use the genus of claimed antibodies as immunotherapeutic agents in vivo much less as any combination in the pharmaceutical composition, one skilled in the art would reasonably conclude that the broadly claimed invention, was not fully supported in the specification, and thereby removing applicants from full possession of the invention.
The rejection is maintained
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
15. The provisional rejection of Claims 1, 5, 22-23, 25-26, 28, 33-34, 37-42, and 45-50 on the ground of nonstatutory double patenting as being unpatentable over claim 55 IV.) of copending Application No. 17/619,569 (reference application US 20220306719) is maintained. Applicants request that the provisional rejection be held in abeyance is granted.
The rejection is maintained.
New Grounds for Objection
Claim Objections
16. Claims 41-42 and 45 are objected to because of the following informalities:
a) Amend claim 41 to recite “[[A]] The pharmaceutical composition of claim 40.” The amendment brings the claim into consistency with the claim set.
b) The numbering of claims 42 and 45 is not in accordance with 37 CFR 1.126 which requires the original numbering of the claims to be preserved throughout the prosecution.
Claims 42 and 45 are amended to depend from claim 46.
When claims are canceled, the remaining claims must not be renumbered. When new claims are presented, they must be numbered consecutively beginning with the number next following the highest numbered claims previously presented (whether entered or not).
Appropriate correction is required.
New Grounds for Rejection
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.
17. Claims 28 and 41 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.
a) Claim 28 is confusing and indefinite for reciting “the polypeptide is” and “the polypeptide is: (d) comprises…”. The claim uses both closed and open language.
b) Claim 41 is indefinite for failure of proper punctuation. The POSA cannot reasonably ascertain the metes and bounds of the claimed subject matter. MPEP 608.01(m). Each claim begins with a capital letter and ends with a period.
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.
Written Description/ New Matter
18. Claims 1, 5, 22-23, 25-26, 28, 33-34, 37-42, and 45-50 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1, 5, 22-23, 25-26, 28, 33-34, 37-42, and 45-50 is amended to replace “An antibody or derivative thereof that binds to human receptor tyrosine kinase-like orphan receptor 2 (ROR2)” with “A polypeptide comprising an antibody binding domain that binds to human receptor tyrosine kinase-like orphan receptor 2 (ROR2)”.
Applicants have not identified support in the specification/drawings for the claim amendment. “Applicant should… specifically point out the support for any amendments made to the disclosure” (MPEP, 2163, II, A). As in the present case, the support for the claim limitation is not apparent, and applicant has not pointed out where the limitation is supported”, the claims lack of adequate written description (MPEP, 2163.04, I).
A search of the specification references the term “polypeptide” in the context of a scFv-Fc format having VH and VL “fused via a polypeptide linker” at [0018].
A search of the specification references the term “antibody binding domain” are taught in the context of an antibody and not just any polypeptide at [0160].
MPEP 706.03(m) states in part "New matter includes not only the addition of wholly unsupported subject matter, but may also include adding specific percentages or compounds after a broader original disclosure, or even the omission of a step from a method. See MPEP § 608.04 to § 608.04(c). See In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976) and MPEP § 2163.05 for guidance in determining whether the addition of specific percentages or compounds after a broader original disclosure constitutes new matter.”
Conclusion
19. No claims are allowed.
20. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
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