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
Status of the Claims
1. Claims 1-21 are the original claims filed on 12/28/2022. In the Preliminary Amendment of 12/28/2022, claims 3-12, 14-17, 19, and 21 are amended, claims 18 and 20 are cancelled, and new claim 22 is added. IN the Reply of 11/4/2025, no claims are amended. Claims 1-17, 19, and 21-22 are all the pending claims.
Election/Restrictions
2. Applicant’s election without traverse of species for treating in the reply filed on 11/4/2025 is acknowledged.
3. Claim 21 species for “preventing” are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/4/2025.
4. Claims 1-17, 19, and 21-22 are the claims under examination.
Priority
5. USAN 18/013,530, filed 12/28/2022, is a National Stage entry of PCT/CN2021 /102935, International Filing Date: 06/29/2021, claims foreign priority to CN 202010618158.0, filed 06/30/2020, claims foreign priority to CN 202010630471.6, filed 06/30/2020, claims foreign priority to CN 202011423832.6, filed 12/08/2020.
Applicant is advised of possible benefits under 35 U.S.C. 119(a)-(d) and (f), wherein an application for patent filed in the United States may be entitled to claim priority to an application filed in a foreign country: CN 202010618158.0, filed 06/30/2020, and CN 202010630471.6, filed 06/30/2020.
It is noted, however, that applicant has not filed a certified copy of the application, CN 202011423832.6, filed 12/08/2020, as required by 37 CFR 1.55. The priority date is granted to the International Filing Date: 06/29/2021.
Information Disclosure Statement
6. As of 1/2/2026, a total of one (1) IDS is filed: 6/8/2023. The corresponding initialed and dated 1449 form is considered and of record. The submission is in compliance with the provisions of 37 CFR 1.97.
Objections
Specification
7. The abstract of the disclosure is objected to because it exceeds 150 words and contains legal phraseology:
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A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
8. The disclosure is objected to because of the following informalities:
a) The use of the term, ATCC, NCBI, UniProt, Alexa, Octet, Tris, nanobody, WinNonlin, GraphPad Prism, FlowJo, FACS, EZ-LINK, Harbour HCAB+, NovoCyte, AffiniPure, TSKgel, NanoDrop, OPTI-MEM, DARPin, WuXibody, DVD-Ig, FIT-Ig, which is a trade name or a mark used in commerce, has been noted in this application. The 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.
b) The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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. See [0121].
Appropriate correction is required.
Claim Objections
9. Claims 1-17, 19, and 21-22 are objected to because of the following informalities:
a) Claims 1-17, 19, and 21-22 are objected to improper punctuation throughout. A semicolon (;) is preceded by a colon (:); a comma (,) is preceded by a comma (,).
b) Amend claim 1 to clarify the construction of the binding protein as follows:
A binding protein comprising at least two protein functional regions,
wherein the binding protein comprises a protein functional region A and a protein functional region B[;], and the protein functional region A and the protein functional region B target different antigens or different epitopes on the same antigen[;],
wherein the protein functional region A is of a Fab structure[;], the protein functional region B is of a VH structure, and the binding protein further comprises an Fc homodimer[;],
wherein the number of the protein functional region A is two, and the number of the protein functional region B is two[;],
wherein the binding protein is of a left-right symmetric structure[;],
wherein the binding protein comprises a protein functional region A, a protein functional region B and an Fc homodimer sequentially from the N-terminus to the C-terminus, and
wherein the protein functional region A is linked to the protein functional region B via a first linker peptide (L1), and the protein functional region B is linked to the Fc via a second linker peptide (L2).
c) Amend claim 2 to replace “;” with “,”.
d) Amend claim 17 to replace “An administration device” with “A device for administering.” See claim 15(i).
e) Amend claim 19 to recite “, in vitro, or in vivo,”.
f) Amend claim 13 as follows:
A method for preparing a binding protein comprising culturing the transformant according to claim 12 under conditions to express the binding protein, and obtaining the binding protein from [a] the culture.
Appropriate correction is required.
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.
10. Claims 2-3, 9, 11-15, 17, and 21 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) Regarding claims 2-3, 9, 11-12, 14-15, 17, and 21, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
b) Regarding claim 2, the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
c) Claim 9 recites the limitation "the heavy chain constant region (CH)…". There is insufficient antecedent basis for this limitation in the claim in depending from claim 1. Claim 1 is not drawn to a heavy chain constant region that is otherwise necessary to provide antecedent basis for claim 14.
d) Regarding claims 12-13 and 17, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
e) Claim 14 recites the limitation "the pharmaceutical composition further comprises an additional anti-tumor antibody as an active ingredient ". There is insufficient antecedent basis for this limitation in the claim in depending from claim 1. Claim 1 is not drawn to an anti-tumor antibody that is otherwise necessary to provide antecedent basis for “an additional anti-tumor antibody” in claim 14.
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.
Scope of Enablement
11. Claim 21 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the Fab-HCAb structure (PR000305, PR000653, PR000654, PR000655 and PR000706) capable of binding to CTLA4, does not reasonably provide enablement for making and using the scope of binding proteins to treat any cancer or other disease in any subject in need thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required, are summarized in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). They include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability of the art, the breadth of the claims, the quantity of experimentation which would be required in order to practice the invention as claimed.
Claim interpretation
Claim 21 is drawn to:
a method for diagnosing, (preventing-withdrawn), or treating cancer or other diseases comprising the step of administering to a patient in need thereof the binding protein according to claim 1; preferably, the cancer is selected from one or more of breast cancer, ovarian cancer, endometrial cancer, renal cancer, melanoma, lung cancer, gastric cancer, liver cancer, esophageal cancer, cervical cancer, head and neck neoplasm, cholangiocarcinoma, gallbladder cancer, bladder cancer, sarcoma, colorectal cancer, lymphoma and multiple myeloma.
“treat”: the specification does not provide a per se definition for the term and variations thereof. The specification does not provide a per se definition for an effective amount or therapeutic amount. Accordingly, in the absence of clarity for the meaning, the term is considered to encompass both therapeutic and prophylactic outcomes.
“other diseases”/ “disease”: the specification does not provide a per se definition for the term and variations thereof. Accordingly, the breadth and scope of the phrase “other diseases” is incalculable and potentially infinite.
Disclosure in the Specification
Example 8:
[0254] In this example, the anti-CTLA4 HCAb monoclonal antibody PR000184 was used as a positive control molecule, and was also the parent monoclonal antibody of the CTLA4 end of HER2×CTLA4.
[0255] As shown in FIG. 15, the bispecific binding proteins with the Fab-HCAb structure (PR000305, PR000653, PR000654, PR000655 and PR000706) were all able to bind to CTLA4. Those molecules had similar structures with the identical VH sequence at the end of CTLA4, with minor differences in the different first linker peptides and hinge regions linking the Fc. Therefore, those molecules had very similar binding ability to CTLA4. This indicates that the length or sequence of different linker peptides has little effect on the binding domain VH in the Fab-HCAb structure.
[0256] In another aspect, those molecules had EC.sub.50 values for binding to CTLA4 that were similar to or 1.5-3 times poorer than the parent monoclonal antibody PR000184, but had lower maximum binding signals (maximum MFIs) on FACS than the parent monoclonal antibody PR000184. This may suggest that in some application scenarios for the Fab-HCAb structure, the Fab domain may have a “masking” effect on the VH domain of the HCAb, so that the Fab-HCAb molecule may preferentially bind to the target recognized by the Fab domain before causing binding of the VH domain. The binding in sequence and the difference in the binding force of different targets can be suitable for the requirements of some special application scenarios. For example, the recommended initial dose of the anti-HER2 monoclonal antibody trastuzumab is 4 mg/kg for the treatment of breast cancer and 8 mg/kg for the treatment of gastric cancer; while the recommended initial dose of the anti-CTLA4 monoclonal antibody ipilimumab was 3 mg/kg for the treatment of melanoma and lower in combination therapy. For the HER2×CTLA4 with the Fab-HCAb structure, the activity of the HER2 end is almost comparable to that of their parent monoclonal antibody, but the activity of the CTLA4 end is relatively weakened. Therefore, this structure can be used to achieve the clinical requirements for moderate or low doses of CTLA4 inhibitors. In addition, HER2×CTLA4 can preferentially bind to HER2 and enriched in tumor tissues highly expressing HER2, so that toxic and side effects caused by non-specific activation of T cells by CTLA4 antibodies in a peripheral system are reduced.
Prior Art Status: Immunotherapeutics especially cancer therapy is unpredictable
The use of antibody immunotherapy for the treatment of tumors has been shown to have limitations. Five (5) art references spanning over 25 years in the field of immunotherapeutics and recognizing 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)); Rudnick et al. (Can. Biotherp. & Radiopharm. 24: 155-162 (2009)); and Huang et al. (Appl Microbiol Biotechnol (2010) 87:401–410).
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.”
Huang supports and substantiates the challenges for recombinant antibodies as immunotherapeutic agents (p. 403 and 408):
“Genetic engineering has long been employed to increase the affinity of mAb to its target by altering the amino acid sequence in complementary determining region (CDR; Maynard and Georgiou 2000; Reff et al. 2002). However, high specificity must be maintained while increasing antibody affinity as it might augment cross reactivity with other nonspecific antigens, causing unwanted side effects (Hu et al. 2009). High-affinity CDR also can be suboptimal for targeting solid tumors; thus, a suitable affinity may need to be determined (Chames et al. 2009).”
“Many hurdles remain, however, due to the complexity of human immunology as demonstrated by our limited success in chronic infectious diseases and cancer. The approach to combine both active and passive immunotherapies to have synergic effects to maximize desired immune responses may lead a way for treatments of these diseases in the near future.”
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)). “Whether undue experimentation is required is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” Streck, Inc. v. Research & Diagnostic Systems, 665 F.3d 1269 (Fed. Cir. 2012)).
The observations set forth above and taken together in view of the absence of extrinsic evidence to support and further enable the scope of the method claims as broadly drawn, and the recognized unpredictability of the immunotherapeutic arts based on the record art references, support and substantiate the position that the ordinary artisan could not practice the full scope of the claimed method absent undue experimentation. (MPEP 716.01 and 2145 (The arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997)).
Claim Rejections - 35 USC § 103
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 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.
Claim(s) 1-3, 9-17, 19, and 21-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Moore (US 2014/0288275, published 09/25/2014 (I)), Timmer (US 2017/0015753, published 01/19/2017), Weidanz (US 2019/0071502, published 03/07/2019), and Eckelman (US 2023/0124851, with priority to 10/11/2018).
Generic claim 1 is drawn to an Fab-HCab (heavy chain antibody) having the structure for (1) a short chain comprising VH_A-CH1 sequentially from the N-terminus to the C-terminus, and a long chain comprising VL_A-CL-L1-VH_B-L2-CH2-CH3 sequentially from the N-terminus to the C-terminus; or (2) a short chain comprising VL_A-CL sequentially from the N-terminus to the C-terminus, and a long chain comprising VH_A- CH1-L1-VH_B-L2-CH2-CH3 sequentially from the N-terminus to the C-terminus.
The claims are prima facie obvious over Moore (I and II), Timmer, Weidanz and Eckelman.
As regards Claim 1, Moore et al is drawn to novel heterodimeric proteins including heterodimeric antibodies (see Abstract). Moore et al disclose that the heterodimeric antibodies of the invention further comprise one or two additional antigen binding domains that can be either or both of an scFv and a Fab (see [0011]).
Moore teaches anti-CD19 binding domains and anti-CD3 binding domains which are Fab and Fv domains, respectively, comprised within a heavy chain antibody that is the first polypeptide of the invention. For example, Figure 8 provides:
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Figure 13D confers a single heavy chain antibody comprising from N- to C-terminus a Fab-Fv (comprising a Vh structure)-Fc comprising a first polypeptidfe. Figure 13D comprises a second polypeptide comprising an Fc region comprising a scfv. Other related molecules are in Figures 12-13. The prototypes taught in Moore are bispecific at least as they bind antigen 1 and 2 (Ag.1-2).
As regards claim 2, specifically, Moore discloses Fig. 12D wherein the heterodimeric protein design depicts an additional Fab attached to the Fab monomer (see [0054] and [0093]). Additionally, Figures 11B and 12D show one chain that has an scFv-hinge-CH2-CH3 while the other chain with Fc region has VH-CH1-hinge-Fc region and that is paired with a third chain comprising VL-CL. Moore discloses linker peptides at [0130; 0234].
AS regards claims 3 and 22, Moore disclose that the heterodimeric proteins can target antigens such as HER2, CTLA4, OX40, BCMA, 4-1BB (see [0185]-[0201]).
As regards claim 9, Moore teaches CL regions for the constructs being lambda or kappa at [0128] By "variable region" as used herein is meant the region of an immunoglobulin that comprises one or more Ig domains substantially encoded by any of the V.kappa., V.lamda., and/or VH genes that make up the kappa, lambda, and heavy chain immunoglobulin genetic loci respectively.
AS regards claims 10-12, Moore teaches nucleic acids, vectors and host cells ([0025] In an additional aspect, the invention provides host cells comprising the expression vectors and nucleic acids encoding the compositions of the invention; and [0040] The present invention provides isolated nucleic acids encoding the novel immunoglobulin compositions described herein. The present invention provides vectors comprising said nucleic acids, optionally, operably linked to control sequences. The present invention provides host cells containing the vectors, and methods for producing and optionally recovering the immunoglobulin compositions.). Moore teaches CHO cells at [0221].
AS regards claim 13, Moore teaches at [0040] The present invention provides host cells containing the vectors, and methods for producing and optionally recovering the immunoglobulin compositions.
As regards claim 14, Moore teaches at [0299] The therapeutic compositions used in the practice of the foregoing methods can be formulated into pharmaceutical compositions comprising a carrier suitable for the desired delivery method. Suitable carriers include any material that when combined with the therapeutic composition retains the anti-tumor function of the therapeutic composition and is generally non-reactive with the patient's immune system. Examples include, but are not limited to, any of a number of standard pharmaceutical carriers such as sterile phosphate buffered saline solutions, bacteriostatic water, and the like (see, generally, Remington's Pharmaceutical Sciences 16th Edition, A. Osal., Ed., 1980); and at [0301] The formulation herein may also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to provide antibodies with other specifcities. Alternatively, or in addition, the composition may comprise a cytotoxic agent, cytokine, growth inhibitory agent and/or small molecule antagonist. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.
AS regards claim 19, Moore teaches numerous examples of assays that detect a specific antigen by way of the antibody construct at [0247; 0290-0298; 0316].
As regards claim 21, Moore teaches the heterodimeric antibodies can be used to treat tumor/cancer cells (see [0191], [0298], [0307]-[0338], Example 4) specifically at [0310] Thus for B cell tumors, the subject may experience a decrease in the so-called B symptoms, i.e., night sweats, fever, weight loss, and/or urticaria. For pre-malignant conditions, therapy with an multispecific therapeutic agent may block and/or prolong the time before development of a related malignant condition, for example, development of multiple myeloma in subjects suffering from monoclonal gammopathy of undetermined significance (MGUS).
Moore differs from a multispecific design that does not use a domain antibody or VHH as one of the binding domains.
As regards claim 1 for a specific VH domain (or VHH), Timmer teaches multivalent antigen binding proteins with VHH domains to include ones with a chain like VHH-linker-VHH-linker-hinge-Fc (0054). They can be multispecific as in Figure 1 in which some are bispecific or multispecific and all use hinges and Fc regions to multimerize chain with various amounts of single domain antibodies/VHHs. It would have been obvious to PHOSITA before the filing of the instant case to substitute the VHH of Timmer for the scFv or Fab of Moore to arrive at a multispecific antibody design with a reasonable expectation of success as the prior art shows clearly that multiple types of binding domains can be used in multispecific antibodies and in various combinations and so the simply substitution of one type of binding domain for another binding domain, all having been used prior in antibody-like molecules is obvious here.
Not only is it obvious owed to simply substitution of one known for another but there is also motivation in the prior art for the swap above.
Weidanz teaches by linking VHH to hinge Fc domains as part of an antibody dimer, the modified antibody is smaller than a conventional antibody and the lower mass leads to better permeability in tissue without increasing renal clearance providing better tumor penetrance (0305).
Thus, it would have also have been obvious to replace the Fab of Moore with the VHH of Timmer and Weidanz to achieve these advantages in an anti-tumor, multispecific antibody. Indeed, single domain antibodies like VHH have been used in such multispecific antibodies before with Fv-containing molecules. See Eckelman at Figure 3A-E.
As regards claim 9, Timmer teaches human IgG antibodies comprising Fc modifications at [0027] In some embodiments, the human IgG1 Fc region is modified at amino acid Asn297 (Boxed, Kabat Numbering) to prevent to glycosylation of the fusion protein, e.g., Asn297Ala (N297A) or Asn297Asp (N297D). In some embodiments, the Fc region of the fusion protein is modified at amino acid Leu235 (Boxed, Kabat Numbering) to alter Fc receptor interactions, e.g., Leu235Glu (L235E) or Leu235Ala (L235A). In some embodiments, the Fc region of the fusion protein is modified at amino acid Leu234 (Boxed, Kabat Numbering) to alter Fc receptor interactions, e.g., Leu234Ala (L234A). In some embodiments, the Fc region of the fusion protein is altered at both amino acid 234 and 235, e.g., Leu234Ala and Leu235Ala (L234A/L235A) or Leu234Val and Leu235Ala (L234V/L235A). In some embodiments, the Fc region of the fusion protein is altered at Gly235 to reduce Fc receptor binding. For example, wherein Gly235 is deleted from the fusion protein. In some embodiments, the human IgG1 Fc region is modified at amino acid Gly236 to enhance the interaction with CD32A, e.g., Gly236Ala (G236A). In some embodiments, the human IgG1 Fc region is lacks Lys447 (EU index of Kabat et at 1991 Sequences of Proteins of Immunological Interest).
AS regards claim 12, Timmer teaches E coli host cells at [0080-0081] and Weidanz teaches TG1 E coli cells as transformants at [0065] and HEK293 cells as transformants at [0268].
AS regards claims 15-17, Weidanz teaches kits comprising the reagent plus a means for administration at [0192-0195] and specifically syringes at [0192].
AS regards claims 3 and 22, Eckelman teaches the heterodimeric proteins can target antigens such as PDL1 at [0614].
Taken together, the combined teachings above clearly render the technical feature common to all claims as well as a basic design of claim 1 obvious. The references combined substantiate the advantages of a Fab-HCab that provide the underpinnings for motivation and reasonable success based thereon: the Fab-HCab antibody format has the ability to target two different antigens simultaneously while avoiding common manufacturing problems like heavy-light chain mis-pairing encountered with other bispecific formats; it integrates the benefits of the smaller, highly penetrative VH or VHH domain with the properties of a conventional Fab, which when linked to an Fc domain provides for half-life extension or immune effector functions; and the ability to bring two targets into close proximity that leads to more potent therapeutic effects, such as more effective tumor cell elimination.
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.
12. Claims 1-17, 19, and 21-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 and 16-21 of copending Application No. 18/013,523 (reference application US 20230303698). The reference application is not afforded safe harbor under 35 USC 121 because it shares no continuity nor a restriction/speciation with the claims of the instant application.
The sequences for the polypeptide chains 1 and 2 encompassed by the claim sets are identical (shown corresponding SEQ ID NO) from ref claim 21 of ‘523 and instant claim 8:
‘530
147
153
136
183
184
155
158
156
159
160
141
142
143
144
145
149
‘523
212
235
202
270
271
194
240
238
X
X
X
X
X
X
X
X
SEQ ID NO: 147/153 = ref SEQ ID NO= 212/235; SEQ ID NO: 136/183 = ref SEQ ID NO=202/270; SEQ ID NO: 147/184 = ref SEQ ID NO: 212/271; SEQ ID NO: 155/158 = ref SEQ ID NO: 194 or 240; SEQ ID NO: 155/156= ref SEQ ID NO: 194 or 238.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
13. Claims 1-17, 19, and 21-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37-48 of copending Application No. 18/002,655 (reference application US 20230322953). The reference application is not afforded safe harbor under 35 USC 121 because it shares no continuity nor a restriction/speciation with the claims of the instant application.
The claim sets are drawn to an anti-BCMA antibody where the structure of the antibody in ‘655 is defined by the VH domain and a heavy chain. To note that the title and abstract of the ref application recite HCab structures as defined by the instant claims.
The anti-BCMA antibodies that share identity between the claim sets:
Ref SEQ ID NO: 272 (e.g. claim 38) = SEQ ID NO:115 (e.g., claim 5):
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494
988
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This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
14. Claims 1-17, 19, and 21-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 25 and 27-44 of copending Application No. 18/002,479 (reference application US 20230242658). The reference application is not afforded safe harbor under 35 USC 121 because it shares no continuity nor a restriction/speciation with the claims of the instant application.
The claim sets are drawn to an anti-4-1BB antibody where the structure of the antibody in ‘479 is defined by the VH domain and a heavy chain.
The anti-4-1BB antibodies that share identity between the claim sets:
Ref SEQ ID NO: 177 (e.g. claim 25) = SEQ ID NO:111 (e.g., claim 5):
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502
1000
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This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
15. Claims 1-17, 19, and 21-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6, 11, 16, 18-19, 22-23, 26, 33-34, 36, 38, 40-41 and 45-50 of copending Application No. 17/765,270 (reference application US 20220411513). The reference application is not afforded safe harbor under 35 USC 121 because it shares no continuity nor a restriction/speciation with the claims of the instant application.
The claim sets are drawn to an Fab-HCab (heavy chain antibody) having the structure for (1) a short chain comprising VH_A-CH1 sequentially from the N-terminus to the C-terminus, and a long chain comprising VL_A-CL-L1-VH_B-L2-CH2-CH3 sequentially from the N-terminus to the C-terminus; or (2) a short chain comprising VL_A-CL sequentially from the N-terminus to the C-terminus, and a long chain comprising VH_A- CH1-L1-VH_B-L2-CH2-CH3 sequentially from the N-terminus to the C-terminus.
The claim sets are drawn to an anti-PD-L1 antibody where the structure of the antibody in ‘270 is defined by the VH domain and a heavy chain.
The anti-PD-L1 antibodies that share identity between the claim sets:
Ref SEQ ID NO: 101 (e.g. claim 11) = SEQ ID NO:108 (e.g., claim 5):
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394
988
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Ref SEQ ID NO: 114 (e.g. claim 11) = SEQ ID NO:118 (e.g., claim 5):
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396
962
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This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
16. Claims 1-17, 19, and 21-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21, 23, 24, and 26 of copending Application No. 18/013,707 (reference application US 20230295324). The reference application is not afforded safe harbor under 35 USC 121 because it shares no continuity nor a restriction/speciation with the claims of the instant application.
The claim sets are drawn to an Fab-HCab (heavy chain antibody) having the structure for (1) a short chain comprising VH_A-CH1 sequentially from the N-terminus to the C-terminus, and a long chain comprising VL_A-CL-L1-VH_B-L2-CH2-CH3 sequentially from the N-terminus to the C-terminus; or (2) a short chain comprising VL_A-CL sequentially from the N-terminus to the C-terminus, and a long chain comprising VH_A- CH1-L1-VH_B-L2-CH2-CH3 sequentially from the N-terminus to the C-terminus.
The claim sets are drawn to an anti-OX-40 antibody where the structure of the antibody in ‘270 is defined by the VH domain and a heavy chain.
The anti-OX40 antibodies that share identity between the claim sets:
Ref SEQ ID NO: 154 (e.g. claim 9) = SEQ ID NO:112 (e.g., claim 5):
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408
962
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This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
17. No claims are allowed.
18. 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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu Julie can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643