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. In the Response of 5/7/2026, Claims 1, 3, 9, 11-15, 17, 19 and 21 are amended, claim 2 is canceled, and new Claims 23-25 are added.
Claims 1, 3-17, 19, and 21-25 are all the pending claims.
Applicants amendment of the claims raises new grounds for rejection. This Office Action is final.
Priority
2. 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’s filing of a certified copy of the application, CN 202011423832.6, filed 12/28/2020, as required by 37 CFR 1.55 is noted along with the certified English translation of 5/7/2026.
Information Disclosure Statement
3. As of 6/22/2026, a total of two (2) IDS are filed: 6/8/2023; and 5/28/2026. 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.
Withdrawal of Objections
Specification
4. The objection to the abstract of the disclosure because it exceeds 150 words and contains legal phraseology is withdrawn in view of the replacement abstract of 5/7/2026.
5. The objection to the disclosure because it contains an embedded hyperlink and/or other form of browser-executable code is withdrawn in view of the deleted hyperlink.
Claim Objections
6. The objections to Claims 1-17, 19, and 21-22 because of informalities is moot for canceled claim 2 and withdrawn for the pending claims in view of the amendments in response to the objections listed under (a)-(f) in the OA of 1/20/2026.
Withdrawal of Rejections
Claim Rejections - 35 USC § 112(b)
7. The rejection of Claims 2-3, 9, 11-15, 17, and 21 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite.
a) The rejection of claims 2-3, 9, 11-12, 14-15, 17, and 21 for the phrase “preferably” is moot for canceled claim 2 and withdrawn for the amened pending claims. .
b) The rejection of claim 2 for the phrase "for example" is moot for the canceled claim.
c) Claim 1 is amended to recite a heavy chain constant region that provides support for amended Claim 9 to recite human heavy chain constant regions.
d) Claims 12-13 and 17 are amended to delete the phrase "such as".
e) Claim 14 is amended to delete the limitation "the pharmaceutical composition further comprises an additional anti-tumor antibody as an active ingredient ".
Claim Rejections - 35 USC § 103
8. The rejection of Claim(s) 1-3, 9-17, 19, and 21-22 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) is moot for canceled claim 2 and withdrawn for the amended pending claims.
Applicants arguments and the amendment of Claim 1 to clarify the inventive structure is a Fab-HCAB are found persuasive.
The Office acknowledges Applicants comments on p. 25 of the Response that “no evidence demonstrates that VHH, when inserted between a known Fab and Fc, can still effectively exert its antigen binding function” as regards the invention being unpredictable.
Objections Withdrawn-in-part/ Maintained-in-part
Specification
9. The specification is amended to rectify the improper use of the term, ATCC, Alexa, Octet, 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.
The objection to the improper use of the term, NCBI, UniProt, Tris, nanobody, and FACS, which is a trade name or a mark used in commerce, is maintained. The results shown herein below are excerpted from the USPTO Trademark Search database.
PNG
media_image1.png
498
806
media_image1.png
Greyscale
PNG
media_image2.png
478
646
media_image2.png
Greyscale
PNG
media_image3.png
804
2110
media_image3.png
Greyscale
PNG
media_image4.png
494
690
media_image4.png
Greyscale
PNG
media_image5.png
530
592
media_image5.png
Greyscale
The objection is maintained-in-part.
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.
Scope of Enablement
10. The rejection of Claim 21 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not reasonably provide enablement for making and using the scope of binding proteins (FAB-HCAB) to treat any cancer or any other disease in any subject in need thereof is maintained. 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 the method claim.
Note: the method for prevention of claim 21 is withdrawn.
Applicants allege that in amending claim 1 the prosecution is expedited in order to understand the Fab-HCAB structure of Figure 1 used in the method invention that corresponds to working embodiments demonstrated in the specification as filed and unlimited to any specific target.
Response to Arguments
A) The method invention is drawn to diagnosing or treating any cancer or other diseases. Applicants’ demonstration of working Fab-HCAB embodiments in the specification are drawn to the treatment of limited cancers for limited FAB-HCAB constructs and not just any disease.
The Patent Act requires that patent applicant describes the invention in explicit terms to enable any person skilled in the art to make and use the invention. 35 U.S.C. 112. Applicants seek over potentially millions of Fab-HCAB structures than the specification teaches how to make and use. The enablement requirement is a crucial aspect of the patent “bargain”: an inventor is granted limited protection from competition in exchange for publicly disclosing their new technology. See the decision in Morse, Incandescent Lamp, and Holland Furniture, establishing the requirement that if a patent claims an entire class or genus of processes, machines, or compositions of matter, the specification must enable a person skilled in the field to make and use the entire class. If a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class. In other words, the specification must enable the full scope of the invention as defined by its claims. The more one claims, the more one must enable. See §112(a); see also Continental Paper Bag Co. v. Eastern Paper Bag Co., 210 U. S. 405 (1908) (“[T]he claims measure the invention.”).
B) Applicants have not responded to the original grounds for rejection from the OA of 1/20/2026 that substantiate the unpredictability of making, testing and using therapeutic antibodies. The Response is incomplete.
“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)).”
C) The claims encompass a single VH domain comprised within the two identical long chains of the Fab-HCAB structure. The Office acknowledges Applicants comments on p. 25 of the Response that “no evidence demonstrates that VHH, when inserted between a known Fab and Fc, can still effectively exert its antigen binding function” as regards the invention being unpredictable.
The current field of art for single domain antibodies (VH dAb for which is instantly claimed) recognizes the potential for these structures in numerous applications as well as the unpredictability of their binding absent some engineering of residues to maintain specificity or stability. See for example, Krah et al. (Immunopharmacology and Immunotoxicology, 38:1, 21-28 (2016)):
“In contrast to the naturally evolved equivalent in camelids and sharks, early studies
revealed that single human VH domains are prone to aggregation and exhibit poor solubility, which is caused by solvent exposure of hydrophobic patches in the absence of an interacting VL domain. The unfavorable properties were tackled in a variety of
mutational approaches and initial attempts aimed at the transfer of VHH key elements that attributed aggregation resistance and good solubility to camelid VHHs.”
“Nowadays, convenient generation of human dAbs with desired properties and specificities has been achieved using molecular evolution approaches (e.g. phage display) and repertoires of naive or synthetic human VH or VL dAbs. However, most of the human dAb affinity reagents have been isolated from synthetic libraries that are
usually constructed with engineered single scaffolds and CDR-based diversities.”
Kim et al. (Biochimica et Biophysica Acta 1844 (2014) 1983–2001):
“Aggregation and denaturation is a concern in the manufacturability and efficacy of human diagnostic and therapeutic antibodies, as antibody aggregation has been implicated in reduced in vivo efficacy and increased immunogenicity [30–33]. Therapeutic antibodies must possess the ability to withstand physical and chemical stresses, and mechanical agitations, such as high protein concentrations, elevated temperature, extreme pH and ionic strength, freeze drying/filtration/centrifugation,
and exposure to detergents, organic solvents and proteases [34].”
“The physical stability of an antibody encompasses both colloidal [35,36] and conformational (thermodynamic) stabilities, which governs an antibody's resistance to aggregation and unfolding. Inter- and intramolecular forces determine a protein's propensity to aggregate — a complex process where proteins form non-native, but energetically favorable states [37]. This process can occur through multiple pathways
depending on the proteins' biophysical properties.”
Applicants have not characterized a sufficient number of antigens much less reduced to practice a reasonable number of Fab-HCABs comprising just any VH domain, and which bind those antigens with therapeutic efficacy towards the treatment of any cancer much less any other disease. The ordinary artisan could reasonably conclude that Applicants are not in possession of the claimed genus of Fab-HCAB meeting all of the structural and functional properties required of the claimed method invention.
Based on the observations set forth above as taken together in view of the absence of extrinsic evidence, the scope of the method claims as broadly drawn is not further enabled. Along with the art-recognized unpredictability of immunotherapy based on the record art references, the analysis as a whole does NOT support nor substantiate the position that the ordinary artisan could 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)).
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.
11. The provisional rejection of Claims 1, 3-17, 19, and 21-22 and 23-25 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) is moot for canceled claim 2 and maintained for the amended pending claims.
Applicants allege the amendment of instant claim 1 to recite a generic structure for a Fab-HCAB distinguishes the invention apart from the ref claims of record.
Response to Arguments
Ref ‘523 not only teaches but claims a structure (4) that resembles the instant claimed structure (1), but teaches identical short- and long- polypeptide pairs that comprise the symmetrical half of the binding protein for a Fab-HCAB structure. Applicants have neither acknowledged nor responded to the technical arguments presented in the table from the OA of 1/20/2026 to establish obviousness doubling patenting. 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.
The provisional rejection is maintained.
12. The provisional rejection of Claims 1, 3-17, 19, and 23-25 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) is moot for canceled 2 and maintained for the amended pending claims.
Applicants allege the amendment of instant claim 1 to recite a generic structure for a Fab-HCAB distinguishes the invention apart from the ref claims of record.
Response to Arguments
To note that the title and abstract of the ref application recite FAB-HCab structures as defined by the instant claims. Ref ‘655 not only teaches a structure (1) that resembles the instant claimed structure (1), but claims a HCAB structure that comprises a VH domain:
PNG
media_image6.png
114
982
media_image6.png
Greyscale
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.
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):
PNG
media_image7.png
494
988
media_image7.png
Greyscale
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The provisional rejection is maintained.
13. The provisional rejection of Claims 1, 3-17, 19, and 23-25 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) is moot for canceled claim 2 and maintained for amended pending claims.
Applicants allege the amendment of instant claim 1 to recite a generic structure for a Fab-HCAB distinguishes the invention apart from the ref claims of record.
Response to Arguments
To note that the ref application teaches Fab-HCAB (Fig 23C) and anti-4-1BB HCAb structures as defined by the instant claims. Ref ‘655 not only teaches a structure (23C) that resembles the instant claimed structure (1), but claims a HCAB structure that comprises a VH domain.
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):
PNG
media_image8.png
502
1000
media_image8.png
Greyscale
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The provisional rejection is maintained.
14. The provisional rejection of Claims 1, 3-17, 19, and 21-25 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) is moot for canceled claim 2 and maintained for the amended pending claims.
Applicants allege the amendment of instant claim 1 to recite a generic structure for a Fab-HCAB distinguishes the invention apart from the ref claims of record.
Response to Arguments
The PD-L1 antibody portion of the binding protein comprises antibodies that share 100% sequence similarity with the heavy and light chain complementarity determining regions (CDRs) of PR000265. The claims of the ref also recite the isolated nucleic acid encoding said binding protein, an expression vector comprising said nucleic acid, a pharmaceutical composition comprising said binding protein, and a method of treating cancer comprising administering said binding protein.
The differences between the claim sets are as follows. The claims of the ref recite portions of the antibodies sharing the same sequences as the PD-L1 antibodies recited in the instant claims. One having ordinary skill in the art at the time of the filing of the invention would have recognized that the same PD-L1 sequences recited in the reference claims could be used to formulate a PD-L1 antibody. Thus, the instant claims are not patentably distinguishable from those of the reference application.
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):
PNG
media_image9.png
394
988
media_image9.png
Greyscale
Ref SEQ ID NO: 114 (e.g. claim 11) = SEQ ID NO:118 (e.g., claim 5):
PNG
media_image10.png
396
962
media_image10.png
Greyscale
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The provisional rejection is maintained.
15. The provisional rejection of Claims 1, 3-17, 19, and 21-25 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) is moot for canceled claim 2 and maintained for amended pending claims.
Applicants allege the amendment of instant claim 1 to recite a generic structure for a Fab-HCAB distinguishes the invention apart from the ref claims of record.
Response to Arguments
The differences between the claim sets are as follows. The claims of the ref recite portions of the antibodies sharing the same sequences as the OX40 antibodies recited in the instant claims. One having ordinary skill in the art at the time of the filing of the invention would have recognized that the same OX40 sequences recited in the reference claims could be used to formulate a OX40 antibody. Thus, the instant claims are not patentably distinguishable from those of the reference application.
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):
PNG
media_image11.png
408
962
media_image11.png
Greyscale
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The provisional rejection is maintained.
New Grounds for Objection
Claim Objections
16. Claims 1, 6-7 and 9 are objected to because of the following informalities:
a) Amend claim 1 to recite “is [[of]] a Fab structure” and “is [[of]] a left-right symmetric structure.”
b) Claims 6-7 are inconsistent for the phrase “the protein functional region B comprises a heavy chain variable region (VH), wherein the VH comprises HCDR1, HCDR2 and HCDR3” (claim 6) and “the protein functional region B comprises a heavy chain variable region with an amino acid sequence” (claim 7). Unless there is a technical distinction one or the other is preferred but not both.
c) Amend claim 9 to delete “in the binding protein” in both instances.
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 4-5, 17 and 23 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) Claims 4-5 each recite the limitations "the __ antibody". There is insufficient antecedent basis for this limitation in the claims. Claims 4-5 depend from claim 3 that is amended to delete the phrase starting with “preferably” and that references an antibody.
b) Claim 17 is indefinite for the phrase “the device for administering comprises a component.” A component is understood to be a part or an ingredient and not the product or device as a whole.
c) Claim 23 is indefinite for the phrase “wherein the L1 and the L2 are independently none.” In depending from amended claim 1, L1 or L2 are required to be a linker peptide, therefore it is unclear how they cannot comprise a peptide sequence.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
18. Claim 8 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 8 recites “The binding protein according to claim 1, comprising two different polypeptide chains: a first polypeptide chain and a second polypeptide chain.” Claim 8 depends from claim 1 that is amended to recite “wherein the binding protein has four polypeptide chains, including two identical short chains and two identical long chains.” Claim 8 does not reference any one of the polypeptide chains of claim 1 and is broadening from the claim it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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
19. Claims 1, 3-5, 9-17, 19, and 21-25 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.
The interpretation of the claims and the Fab-HCAB format for amended claim 1 is discussed herein throughout the Office Action. The Office acknowledges Applicants comments on p. 25 of the Response that “no evidence demonstrates that VHH, when inserted between a known Fab and Fc, can still effectively exert its antigen binding function” as regards the invention being unpredictable.
The genus of Fab-HCAB constructs encompassed by the claims is beyond those taught in the specification. Because applicant seeks patent protection for all such constructs, this genus must be adequately described. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
Scope of the claimed genus
The discussion of the Fab-HCAB working embodiments from the enablement rejection herein above is incorporated by reference for purposes of brevity.
State of the Relevant Art
By the time the invention was made, it is well-established in the art that the formation of an intact antigen-binding surface on an antibody required the association of the complete heavy and light chain variable regions, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope (Almagro & Franssen, Frontiers in Bioscience, 13:1619-33 (2008) (PTO-892) (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While this overall architecture is shared among antibodies from a wide variety of sources (human, rat, mouse, rabbit), the structure each antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level, even when the same antigen is bound (Edwards et al., J Mol Biol 334:103-118 (2003) (PTO-892); see also Marchalonis et al., Dev & Comp Immunol. 30:223-247 (2006) (PTO-892), summarized in Abstract and Conclusion.
Methods of preparing antibodies from a variety of species to a protein or peptide of interest were well-established in the art at the time the invention was made. But application of those methods to any given antibody was still a matter of trial-and-error testing, and the skilled person could not automatically predict which residues in the CDRs would be tolerant of mutations, or which amino acid substitutions would maintain antigen binding. Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. For example, it is generally the case that absent the fundamental structure provided for by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, a person of ordinary skill cannot visualize or otherwise predict, what an antibody with a particular set of functional properties would look like structurally.
Moreover, persons of ordinary skill in the art have long since acknowledged that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function. Moreover, persons of ordinary skill in the art have long since acknowledged that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function. Lippow, for example, teaches that a single point mutation in the CDR of a parent antibody led to as much as an eightfold improvement in binding affinity in the resulting mutant (p. 1172, left col., lines 7-8 from end of first full paragraph and Table 1a) (Lippow et al., “Computational design of antibody-affinity improvement beyond in vivo maturation,” Nature Biotechnology, 25(10):1171-1176 (2007) (PTO-892).
Sulea teaches that individual point mutations gave an improvement of one order of magnitude in binding affinity, which in turn, generated a 6-fold enhancement of efficacy at the cellular level (Abstract) (Sulea et al., “Application of Assisted Design of Antibody and Protein Therapeutics (ADAPT) improves efficacy of a Clostridium difficile toxin A single-domain antibody," Scientific Reports, 8(260):1-11 (2018) (PTO-892). Hasegawa et al. reports that a single amino acid substitution in the variable region was sufficient to alter the efficiency of biosynthesis and the variant antibody acquired stronger binding affinity to its antigen than the parent (Hasegawa et al., “Single amino acid substitution in LC-CDR1 induces Russell body phenotype that attenuates cellular protein synthesis through elF2a phosphorylation and thereby downregulates IgG secretion despite operational secretory pathway traffic,” MABS, VOL. 9, NO. 5, pp. 854-873 (2017) (PTO-892)). Altshuler teaches that generally, “CDR mutations should not involve residues that can play structural functions (form parts of the domain ‘internal core’, internal salt bridges, hydrogen bonds, etc.).” “Usually these are conservative residues, and any substitution of these residues causes decrease[s] in affinity” (Altshuler et al., “Generation of Recombinant Antibodies and Means for Increasing Their Affinity,” Biochemistry (Moscow), 75(13):1584-1605 (2010) at p. 1600, col. 1, para. 2, lines 1-5 (PTO-892). Accordingly, a person of ordinary skill in the art would have recognized that it was highly unpredictable that any of the CDRs or FRs could be modified to create an unlimited change in amino acids for both the CDRs and FRs of the claimed antibodies, without increasing, eliminating, or in some way altering antigen binding.
Are the disclosed species representative of the claimed genus?
It is asserted that the disclosed species are not representative of the claimed genus because the claims encompass any antigen known and yet to be discovered.
Yet the specification does not identify which CDRs, which combination of fewer than all six CDRs, or which subset of residues in the combination of CDRs is essential for the recited function of the genus of Fab-HCAB. Neither the specification nor the prior art provides guidance as to what structural changes can be made to the parent sequences and still predictably arrive at an antibody that binds any antigen. The disclosed species therefore do not represent the claimed genus.
Has Applicant provided a common structure sufficient to visualize the genus?
Applicant has not provided a common structure sufficient to visualize the genus of all possible functionalized Fab-HCAB constructs.
While the prior art contains disclosure as to the structural features of several anti- antibodies, it is unclear what structural features these antibodies need to share in order to maintain binding affinity and stability. In fact, therapeutic antibodies are still not understood well enough to allow researchers to predict with certainty what modifications can be made to a primary antibody sequence such that binding is maintained. “[T]he major test of understanding is whether the changes associated with antibody maturation can be predicted with any reasonable accuracy, and whether there is sufficient information for developing therapeutic antibodies,” Vajda et al., “Progress toward improved understanding of antibody maturation,” Current Opinion in Structural Biology, 67 pp. 226-231 (2021 (PTO 892)) at p. 226, col. 2, lines 20-24.
As recently as 2020, researches were still speculating as to how to reliably identify further putative binders from antibody sequence data, see, e.g., Marks et al., “How repertoire data are changing antibody science,” J. Biol. Chem. 295(29) 9823-9837 (2020 (PTO 892)), acknowledging that “there is a vast amount of the antibody sequence space that remains unknown,” p. 9831, col. 2, para. 2.
Even if the protein sequence of any given antigen was known in the art, this would not have translated into knowledge of the genus of antibodies that could possibly engage it. Computational and machine learning approaches for sequence-based prediction of paratope-epitope interactions are accumulating, but “it remains unclear whether antibody-antigen binding is predictable” (Akbar et al., Cell Reports 34, 108856, Mar. 16, 2021 at p. 2, col. 2, para. 2 (PTO 892)). The current state of the art continues to work toward finding an effective and efficient prediction tool for reliably assigning antibody structure based on known target epitopes. See e.g., Lo et al., “Conformational epitope matching and prediction based on protein surface spiral features,” BMC Genomics volume 22, Article number: 116 (2021 (PTO 892)) (disclosing new algorithms that calculate physicochemical properties, such as polarity, charge or the secondary structure of residues within the targeted protein sequences, and then applying quantitative matrix analyses or machine-learning algorithms to predict linear and conformational epitopes).
Regarding a representative number of species, the instant specification fails to describe a representative number of species to provide adequate written description of the claimed genus as per MPEP § 2163. The specification describes a limited number of species of Fab-HCBA constructs demonstrating a structure correlated with a function(s) as required by the claims.
Applicant’s attention is directed to the decision in Amgen Inc. v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The court discussed whether an antibody is adequately described by describing a newly characterized antigen. Specifically, the court referred to the decision in Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341 (Fed. Cir. 2011). In Centocor Ortho Biotech Inc. v. Abbott Labs., No. 2010-1144 (Fed. Cir. 2/23/2011) the Federal Circuit noted that the ‘775 specification only includes a mouse variable region and does not disclose a single human variable region. The court further stated that Centocor’s mouse variable region was “very different” from the sequence of a human variable region, and that the specification does not “disclose any relationship between the human TNF-α protein, the known mouse variable region that satisfies the critical claim limitations, and potential human variable regions that will satisfy the claim limitations.” Therefore, the mouse variable region did not serve as a “stepping stone” to identifying a human variable region within the scope of the claims.
It is asserted that neither the specification nor the state of art at the time of filing disclosed structural features common to the members of the genus Fab-HCAB as instantly claimed for reliably assigning different antibody structures based on sequence data for a limited number of constructs, which would support the premise that the inventors possessed the full scope of the claimed invention.
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.
20. Claim(s) 1, 3, 9-17, 19, and 21-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al (US-11713353) as evidenced by Shi (www.genscript.com/learning-center/crossmab-when-light-and-heavy-chains-learn-to-find-their-right-places.html; May 12, 2025)
The claims are prima facie obvious over Zhang.
AS regards claim 1, Zhang teaches a Fab-HCAB structure in Figure 22:
PNG
media_image12.png
620
862
media_image12.png
Greyscale
comprising left-right symmetric pairing of a short chain comprising a VL-CL and a long chain comprising a VH-CL-L1-VH-L2-CH2-CH3. The exchange between a VL-CH1 and a VH-CH1 in the Fab of the instant claim 1, otherwise known as a cross-mab fab, is obvious as evidenced by Shi because light chains can mispair with the wrong heavy chains. By swapping the entire heavy-chain domain with the light-chain domain forces the heavy and light chains to find their correct, cognate partners. They can no longer pair incorrectly because it would result in incompatible heavy-heavy or light-light alignments. Accordingly, the invention of claim 1 is a cross-mab Fab-HCAb.
As regards claim 3, Zhang teaches antigens for PD-L1, CTLA4 at (24).
As regards claim 9, Zhang teaches human antibodies at (8)
As regards claims 10-13, Zhang teaches nucleic acids at (25), vectors at (26), host cells at (27) and method of expression at (29).
AS regards claim 14, Zhang teaches pharmaceutical compositions at (23).
As regards claims 15-16, Zhang teaches kits at (28).
AS regards claim 17, Zhang teaches injection devices; injector pens; auto-injector devices, needleless devices; and subcutaneous patch delivery systems at (285).
AS regards claim 19, Zhang teaches detection or diagnosis at (276).
AS regards claim 21, Zhang teaches methods of treating cancer or other diseases such as immune-related disease at (24).
AS regards claims 22 and 24, Zhang teaches the combination of targeting PD-L1 and CTLA4 at (24), (28).
As regards claim 23, Zhang teaches linker peptides at (18) and (19) and (203)-(206).
AS regards claim 25, Zhang teaches kappa and lambda chains at (41) and IgG isotypes at (41).
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 cross mab 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.
Conclusion
21. No claims are allowed.
22. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
23. 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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, 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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643
Prosecution Insights