DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s election without traverse of Group I (drawn to a coagulation factor XI) and the species of SEQ ID NO:14 for the first VHH and SEQ ID NO:17 for the second VHH in the Response filed on July 2, 2026 is acknowledged.
Claims 33-35, 39, 40, and 45 have been canceled.
Claims 1-31. 32, 37, and 41-44 are pending.
Claims 3-6, 14, 15, 18, 19, 32, 37, and 41-44 have been withdrawn under 37 CFR 1.142(b) as being drawn to nonelected invention/species.
Claims 1, 2, 7-13, and 16, 17, and 20-31 are currently under consideration as they read on the elected invention.
3. This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 for the reason(s) set forth herein.
Upon review of the instant application, it is noted that the nucleotide sequences disclosed at least on page 32 are not accompanied by SEQ ID Numbers. Applicant is reminded of the sequence rules which require a submission for all sequences of more than 9 nucleotides (see 37 CFR 1.821-1.825) and is also requested to carefully review the submitted specification for any and all sequences which require compliance with the rules. Applicant is reminded to amend the specification and the claims accordingly.
Applicant must comply with the requirements of the sequence rules (37 CFR 1.821 - 1.825) in response to this Office Action.
4. 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.
5. Claims 21 and 30 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.
Regarding claims 21 and 30, the phrase “preferably a human immunoglobulin Fc region, such as an Fc region of human IgG1, IgG2, IgG3, or IgG4" 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).
6. 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.
7. Claims 23, 24, 29, 30, and 31 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 claims are drawn to a coagulation factor XI (FXI) binding protein comprising a first immunoglobulin single variable domain and a second immunoglobulin single variable domain, each capable of specifically binding to FXI to a different epitope on FXI.
The specification discloses that anti-FXI antibodies were screened from camel blood immunized with human FXI (e.g. see Example 1 in page 27 of the specification as-filed). The specification further discloses twenty-three anti-human FXI VHH antibodies (e.g. see pages 11-12 and Table 1 in page 30 of the instant specification as-filed).
There is insufficient written description in the specification as-filed of the claimed genus of FXI binding protein. The claims recite a genus of FXI binding protein without providing physical structure that would correlate with the function of FXI binding. The genus of the FXI binding proteins is therefore extremely large.
Applicant has disclosed only specific VHH antibodies having defined amino acid sequences. Thus, Applicant has disclosed only a limited species of the FXI binding protein, namely VHH having amino acid sequences. The claimed FXI binding proteins lack a common structure essential for their function and the claims do not require any particular structure basis or testable functions be shared by the instant FXI binding proteins.
It was known in the art that VHH engineering can be unpredictable. For example, De Genst et al. (Developmental and Comparative Immunology 30(2006) 187-198) teach that the VHH amino acid sequences resembles closely to that of a human VH of family III, with notable differences in its FR2 and CDRs in that the hydrophobic amino acid residues in the human VH FR2 region (e.g. the highly conserved Val42) was replaced with more hydrophilic resides in VHH (Phe42) and the conserved hydrophobic amino acid residues in the VHH FR2 region are important in maintaining the solubility of the isolated VHH domain (e.g. see page 188).
De Genst et al. further teach that since the three antigen binding loops provided by a VL are absent in the antigen-binding site in the VHH, the three CDRs of the VHH are critical for antigen binding specificity and affinity and that cloning VHH antibody (e.g. by phage display or camelizing CDR3 by using a synthetic library) can be disadvantageous since lower affinity binders are often obtained that need additional mutagenesis steps (e.g. see right column on page 188 and left column on page 196).
Tereshko et al. (Protein Science. 2008, 17:1175-1187), in engineering VHH that binds RNase from yeast surface display system, teach that only a small fraction of the library was both expression and antigen-binding, indicating that some of the mutations or combinations thereof are detrimental to the VHH antigen binding and stability (e.g. see pages 1176-1178).
Deschacht et al. (The Journal of Immunology, 2010, 184:5696-5704) teach that the llama H chain antibody (HCAbs) differs from the VH domain of classical antibodies only by a few crucial substitutions of the amino acid normally involved in VL parings with hallmark residues located in FR2 with additional key residues located in CDR loops for maintaining antigen binding and soluble behavior and the inherent hypervariable character (in length and sequence of the CDR regions precludes identification of the critical residues (e.g. see pages 5696 and 5702-5703).
Sircar et al. (The Journal of Immunology 2011, 186:6357-6367) teach that the CDRs of the VHH antibody adopt diverse conformations not classifiable by established canonical rules and thus, VHH structures with biological relevant conformations of the unique CDR loops are required to understand VHH-antigen interaction (e.g. see pages 6357-6358).
Further, while it is not required that all potential embodiments be disclosed, the written description doctrine requires that sufficient representing species be disclosed in order to support the entire genus. Rather than simply listing various embodiments, the usual approach is to also describe common structural features of the species. See Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559 (Fed. Cir. 1997) and Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010).
In Abbvie Deutschland Gmbh & Co KG, Abbvie Bioresearch Center, Inc.,and Abbvie Biotechnolo~, Ltd., v. Janssen Biotech In. And Centocor Biologics,LLC, Case No. 2013-1338 and 2013- 1346, C.A.Fed. ("Abbvie"), the Federal Circuit reiterates the inherent unpredictability of protein engineering in Abbvie. For example, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Ariad, 598 F.3d at 1351 ("[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology."); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein). It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem, Inc. v. Gen- Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002). However, the record here does not indicate such an established correlation. Instead, AbbVie used a trial and error approach to modify individual amino acids in order to improve the IL-12 binding affinity.”
In Novozymes A/S et al. v. Dupont Nutrition Biosciences APS et al., 2013 WL3779376, Case No. 2012-1433, C.A.Fed. (Wis.), the court states:
“The effects of any given mutation or combination of mutations in a variant can differ depending on the position(s) modified and the specific mutation implemented at each position. Some mutations may have no discernible effect on enzyme function, somemay lead to varying degrees of instability or functional impairment, and some may actually improve enzyme activity or impart other desirable properties, such as improved stability at high temperatures.” Page 5.
Here, it does not appear based upon the limited disclosure of full length FXI VHH antigen-binding proteins with specific amino acid sequences for all three CDRs alone that Applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the limited number of species disclosed and the extensive variation permitted within the genus of VHH-binding protein.
“Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Regents of the University of California v. Eli Lilly and Co. 43 USPQ2d 1398 (Fed. Cir. 1997).
The disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter of the claim. Id. 43 USPQ2d at 1406.
In the absence of disclosure of relevant, identifying characteristics of the FXI binding protein (namely the amino acid sequences of CDR1, CDR2 and CDR3), there is insufficient written disclosure under 35 U.S.C. 112, first paragraph for the claimed FXI binding protein.
8. 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.
9. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
10. Claims 23, 24, 29, and 30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Eder et al. (US 2018/0355056, reference on IDS).
Eder et al. teach anti-human FXI antibodies (see title). Eder et al. teach that the antibody can be single variable domain antibody VHH which is low molecular weight and extremely thermostable, stable to extreme pH and proteolytic digestion (e.g. see [0301]-[0304]). Eder et al. further teach that the VHH can be produced by well-known established methods such as from camelid animals or from a library of phage display (e.g. see [0304]). Eder et al. also teach that the antibody can be bispecific where one anti-FXI antibody is linked to another and the bispecific antibody binds at least two different binding sites of the FXI (e.g. see [0306]-[0307]).
Eder et al. teach anti-human FXI antibody that binds the paratope on FXI in residue 27 (A1) to residue 105 (A2). Therefore, the reference teachings anticipate the instant invention.
11. 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, 2, 7-13, 16, 17, and 20-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 8, 10, 11, 13, 17-19, 24, 27-33 of copending USSN 18/714,678 (the ‘678 application).
The instant claims are drawn to a FXI binding protein comprising at least a immunoglobulin single variable domain comprising SEQ ID NO:14 and/or SEQ ID NO:17.
The claims in the ‘678 application are drawn to a method for preventing and/or treating a thromboembolic disease by administering a FXI binding protein comprising a first immunoglobulin single variable domain comprising the three CDRs from SEQ ID NO:14 and a second immunoglobulin single variable domain comprising three CDRs from SEQ ID NO:17.
Although the claims at issue are not identical, they are not patentably distinct from each other because both the instant claims and the copending claims are drawn to the same or nearly the same FXI binding protein comprising the same amino acid sequences. The instant SEQ ID NO:14 is 100% identical to the SEQ ID NO:14 recited in the copending claims, see sequence alignment below:
US-18-714-678-14
Sequence 14, US/18714678
Publication No. US20250034277A1
GENERAL INFORMATION
APPLICANT: SUZHOU ALPHAMAB CO., LTD. (en)
TITLE OF INVENTION: METHOD FOR PREVENTING AND/OR TREATING THROMBOEMBOLIC DISEASES (en)
FILE REFERENCE: 262790-548036
CURRENT APPLICATION NUMBER: US/18/714,678
CURRENT FILING DATE: 2024-05-30
NUMBER OF SEQ ID NOS: 350
SEQ ID NO 14
LENGTH: 130
TYPE: PRT
FEATURE:
NAME/KEY: REGION
LOCATION: 1..130
QUALIFIERS: note = Artificial Sequence
FEATURE:
NAME/KEY: source
LOCATION: 1..130
QUALIFIERS: mol_type = protein
organism = synthetic construct
Query Match 100.0%; Score 691; Length 130;
Best Local Similarity 100.0%;
Matches 130; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLQESGGGSVQAGGSLRLSCAASGHTYSSNYCMAWFRQAPGKEREGVAAIYSDGSTSY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLQESGGGSVQAGGSLRLSCAASGHTYSSNYCMAWFRQAPGKEREGVAAIYSDGSTSY 60
Qy 61 ADSVKGRFTISKDNAKNTLYLQIDSLKPEDTSLYYCAATAYEGSWTGKQPLCLLYEYTYW 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISKDNAKNTLYLQIDSLKPEDTSLYYCAATAYEGSWTGKQPLCLLYEYTYW 120
Qy 121 GQGTQVTVSS 130
||||||||||
Db 121 GQGTQVTVSS 130
The instant SEQ ID NO:17 is 100% identical to the SEQ ID NO:17 as recited in the copending claims, see sequence alignment below:
US-18-714-678-17
Sequence 17, US/18714678
Publication No. US20250034277A1
GENERAL INFORMATION
APPLICANT: SUZHOU ALPHAMAB CO., LTD. (en)
TITLE OF INVENTION: METHOD FOR PREVENTING AND/OR TREATING THROMBOEMBOLIC DISEASES (en)
FILE REFERENCE: 262790-548036
CURRENT APPLICATION NUMBER: US/18/714,678
CURRENT FILING DATE: 2024-05-30
NUMBER OF SEQ ID NOS: 350
SEQ ID NO 17
LENGTH: 126
TYPE: PRT
FEATURE:
NAME/KEY: REGION
LOCATION: 1..126
QUALIFIERS: note = Artificial Sequence
FEATURE:
NAME/KEY: source
LOCATION: 1..126
QUALIFIERS: mol_type = protein
organism = synthetic construct
Query Match 100.0%; Score 678; Length 126;
Best Local Similarity 100.0%;
Matches 126; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLQESGGGSVQAGGSLRLSCTASEFTFDDSDMAWYRQAPGNECELVSTITSDGGTYYA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLQESGGGSVQAGGSLRLSCTASEFTFDDSDMAWYRQAPGNECELVSTITSDGGTYYA 60
Qy 61 DSVKGRFTISQDNAKNTMYLQMNNLKPEDTAVYYCAADQWGSAEGDCTSSYPGGYWGQGT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DSVKGRFTISQDNAKNTMYLQMNNLKPEDTAVYYCAADQWGSAEGDCTSSYPGGYWGQGT 120
Qy 121 QVTVSS 126
||||||
Db 121 QVTVSS 126
Therefore, the FXI binding protein used in the method of treating and/or preventing a thromboembolic disease in the copending ‘678 application would anticipate the instant invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
13. A FXI binding protein comprising at least one immunoglobulin single variable domain of comprising CDRs1-3 of VHH of SEQ ID NO:14 and/or CDRs1-3 of VHH of SEQ ID NO:17 is free of the prior art.
14. No claim is allowed.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHUN W DAHLE/Primary Examiner, Art Unit 1641
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