DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
1. The Election filed July 10, 2026, in response to the Office Action of January 12, 2026, is acknowledged and has been entered. Applicant's election with traverse of Group I, claims 1-15 and the species SEQ ID NO: 2, Nb2 and SEQ ID NO: 56 is acknowledged.
Applicant argues that Group II (claims 16, 18 and 19) and Group III (claims 20-22) are drawn to processes for use of the product in Group I. Thus, the claims of Group II and III have unity under 37 CFR 1.475(b)(2).
Applicant argues at the very least, the claims of Groups I-III have unity of invention due to the related subject matter. Applicant respectfully submits that there would not be an undue burden on the Examiner if all claims are searched and examined together.
Applicant’s arguments have been considered but have not been found persuasive. The claims were not found to lack unity of unity of invention "a priori," i.e., because there is no subject matter common to all claims. Rather the claims were found to lack unity of invention "a posteriori," in view of Walker et al. (Platelets June 2009, 20(4): 268-276, IDS) who teaches a single domain antibody/nanobody against GPVI, BLO8- 1. See abstract, p. 270-left column, and p. 271-right column and Fig. 2. Therefore, the technical feature linking the inventions of Groups 1-3 does not constitute a special technical feature as defined by PCT Rule 13.2 as it does not define a contribution over the prior art. Therefore, Applicant’s arguments with respect to lack of unity are not found persuasive.
Regarding burden of search, the instant application is a National Stage application filed under 35 U.S.C. §371 and the restriction of the various groups is determined with respect to unity of invention as covered in chapter 1800 of the MPEP. See MPEP § 801, not burden of search.
For these reasons the restriction requirement is deemed to be proper and is therefore made FINAL.
2. Claims 1-16 and 18-22 are pending.
3. Claims 16 and 18-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
4. Claims 1-15 are currently under consideration. SEQ ID NO: 2, SEQ ID NO: 56, and NB2 were found to be free of the prior art. Thus, the other nanobody species were rejoined for search and consideration.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
5. Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). See p. 6-2nd paragraph, p. 18-last line, and p. 22-2nd paragraph.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Drawings
6. The drawings are objected to because: 1) The Nb2 CDR3 sequence in Fig. 6B should be labeled with SEQ ID NO: 118; 2) In Fig 8, the top portion of the figure is labeled with “a)”, but “a)” is not recited in the description of Figure 8; 3) There are ten figures in the drawings, but the description of the drawings contains descriptions of Figures 11-13.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
7. The use of the term nanobody, which is a trade name or a mark used in commerce (see NANOBODY (Ser. No. 85573029, Reg. Date Dec. 13, 2016) and NANOBODIES (Ser. No. 79004985, Reg. Date Dec. 20, 2005)), 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.
Claim Objections
8. Claim 8 is objected to because of the following informalities: The reference to Table 1 is objected to because where possible, claims are to be complete in themselves. See MPEP 2173.05(s). 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.
9. Claims 1-15 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.
Claims 1-15 contain the trademark/trade name nanobody (see NANOBODY (Ser. No. 85573029, Reg. Date Dec. 13, 2016)). Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a single domain antibody, accordingly, the identification/description is indefinite.
Regarding claim 3, the parenthetical phrase including "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).
Claim Rejections - 35 USC § 112
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.
10. Claims 1-15 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.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus take into account the state of the art at the time of the invention. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
On 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies, which can be found at www.uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen. Accordingly, the instant claims have been evaluated in view of that guidance.
Scope of the claimed genus
The claims are broadly drawn to a nanobody, or an antigen binding fragment thereof, which is capable of specifically binding GPVI. The nanobody, or an antigen binding fragment thereof, include nanobodies or fragments thereof that include only the CDR3 domain or less than that. See claim 8. Additionally, the nanobody, or an antigen binding fragment thereof, include nanobodies or fragments thereof include nanobodies that are variants or mutants of the disclosed nanobody sequences. See claims 6 and 7. Further the antibodies are defined by binding to an epitope of GPVI even though the epitope is not defined. See Claim 9.
The specification teaches at p. 7-last paragraph:
The nanobody of the present invention refers to a polypeptide including the above CDR regions having GPVI protein binding activity. The term also encompasses variant forms of polypeptides comprising the above CDR regions that have the same function as the nanobodies of the disclosure. These variations include, but are not limited to, deletion insertions and/or substitutions of one or several (usually 1-50, 1-30, 1-20, or 1-10) amino acids, and addition of one or several (generally less than 20, less than 10, or less than 5) amino acids at C-terminus and/or N-terminus.
Thus, the claims are broadly drawn to a large genus nanobodies, or antigen binding fragments thereof, which are capable of specifically binding GPVI that bind to undefined GPVI epitopes and are variants or mutants of the disclosed nanobody sequences and polynucleotide molecules encoding them.
State of the Relevant Art
Henry and MacKenzie (MABS 2018 10(6): 815-826) teach that single-domain antibodies (sdAbs), are the monomeric binding domains of heavy chain-only antibodies, which have evolved to bind antigen using only three complementarity-determining region (CDR) loops rather than the six present in conventional antibodies. See Abstract and Introduction and Figure 1. Henry and MacKenzie teach that although structural studies of sdAbs have been conducted the specific mechanism of sdAb antigen recognition may differ significantly from conventional antibodies and the mechanism remains unclear. See p. 815-2nd paragraph. Henry and MacKenzie teach that VHH domains bear unusually long CDR3 loops in comparison with human and murine conventional antibodies and VHH genes encode non-canonical disulfide linkages formed between cysteine residue pairs. See Box 1 and Box 2.
Overall, at the time the invention was made, the level of skill for preparing nanobodies and then selecting those nanobodies with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure provided by all three CDRs of a nanobody in the context of appropriate framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what an antibody with a particular set of functional properties would look like structurally.
Summary of Species disclosed in the original specification
The specification teaches the isolation of 54 GPVI nanobodies comprising SEQ ID NOs: 1-54. See Results, pp. 27-34.
The specification teaches that the nanobodies were categorized into 33 distinct binding classes based on their CDR3 region. The nanobodies were categorized into strong, moderate, or weak binders of GPVI. See p. 28-2nd paragraph and Fig. 1b).
Are the disclosed species representative of the claimed genus?
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The specification discloses the reduction to practice 54 GPVI nanobodies comprising SEQ ID NOs: 1-54 of distinct structure and binding activity. The specification does not actually produce any variants of the isolated nanobodies or fragments thereof lacking 1 or more of the CDR domains which retain binding activity to GPVI. Nanobodies produced by different methods, such as in different species or in phage or to different epitopes of GPVI, would have been generally expected to be highly structurally diverse, particularly in the CDR sequences. Thus, while Applicant has described 54 species within claimed genus, genus is very large and Applicant has not produced any variants or fragments of the disclosed nanobodies, which bind to GPVI. The species described therefore cannot be considered representative of the recited genus of GPVI nanobodies recited in the claims. See e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet this requirement in the instant case, the specification must describe structural features that convey the claimed binding activity, a prerequisite for utility in the recited methods of treating.
As noted above, the art generally accepted that the combination of the CDRs within the VH of an a nanobody were essential for binding specificity. But the specification does not describe what residues within the CDRs confer the binding activity claimed. Accordingly, the skilled artisan would not be able to discern a structure/function correlation for antibodies other than those comprising either all 3 CDRs (in the context of VH) of one parental nanobody.
For the reasons presented above, one of skill in the art would not know which of the countless other nanobodies encompassed by the claims that meet the highly general structural requirements of the claims would also be able to specifically bind GPVI. Neither the specification nor the dependent claims provide sufficient additional structure or a structure/function correlation to provide an adequate written description of the genus claimed. Therefore, the skilled artisan would not reasonably conclude that the inventors, at the time the application was filed, had full possession of antibodies as broadly claimed. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, Applicant was not in possession of the invention as claimed.
Claim Rejections - 35 USC § 102
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.
11. Claim(s) 1, 3, 8, 9, 10, 13, 14 and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pallini, C. (GPVI receptor spatial organisation and signalling in platelets. A thesis submitted to the University of Birmingham for the Degree of Doctor of Philosophy, Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham. 280 pages, September 2019, IDS) “Pallini”.
Pallini teaches generation of nanobodies to GPVI with a phage display VHH library. See pp. 78-79 and Fig. 2.2.
Pallini teaches 20 nanobodies belonging to different CDR3 groups were expressed in TGI E. coli strain. Pallini teaches the remaining 34 nanobodies were expressed from a pMECS nucleic acid vector which adds an AAA linker, an HA tag, a His6 tag and gene III of M13 phage to the nanobodies. See pp. 81-84 and 193-201 and Figs. 2.3 and5.2-5.5
Pallini teaches making an Alexa Flour 647 (a diagnostic molecule or tag) conjugated SNAP tagged anti-GPVI nanobodies expressed from the SNAP-tag nucleic acid vector.. See p. 88-91.
Regarding claim 3, Pallini teaches testing. the binding the nanobodies to GPVI D1, Ser22-Thr108, and GPVI D2 Pro114-Thr203. See § 2.6.2-p. 86-87. Pallini teaches that nanobody #14, Nb#14, did not bind GPVI D1 or D2 and likely binds at the interface of D1 and D2. See p. 199-2nd paragraph and Fig. 5.5D. Given that Nb#14 does not bind GPVI D1, Ser22-Thr108, it would not bind residues R38, E40, R67, Q71 or W76,
Regarding claim 9, the claim reads on a nanobody cross-competing with itself and binding to the same epitope as itself.
It is noted that the recitation of “a pharmaceutical formulation” in claim 15 is only suggestive of an intended use that does not result in a structural difference between the claimed invention and the prior art to patentably distinguish the claimed invention from the prior art and thus is not given weight for comparison of the claims with the prior art.
12. Claim(s) 1 and 8-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2009/0130021 A1 (Munch et al. May 21, 2009, IDS), “Munch”
Munch teaches agents which interfere with the binding of GPVI to various components, like fibronectin and vitronectin. See abstract and ¶¶ 0012-0017
Munch teaches the GPVI interfering agents include single domain antibodies, i.e. a nanobody or VHH, which bind GPVI. See ¶¶ 0095-0096, 0197-0198, and 0201.
Regarding claim 8, single domain antibodies comprise CDR1, CDR2 and CDR3 domains. See Table 1 of the current specification.
Regarding claim 9, the claim reads on a nanobody cross-competing with itself and binding to the same epitope as itself.
Regarding claims 10-13, Munch teaches the agents include fusion proteins of antibody derived polypeptides including antibody constant domains, i.e. the Fc domain, to prolong plasma half-life. See ¶¶ 00263-0265. The Fc domain could function as a tag or diagnostic molecule. Munch also teaches cytotoxic drug or toxin conjugates. See ¶¶ 0588.
Regarding claim 14, Munch teaches nucleic acid vectors for expressing the proteins of the invention. See ¶¶ 0145-0149 and 0299-0304.
Regarding claim 15, Munch teaches making pharmaceutical compositions with pharmaceutically acceptable carriers with the agents of the invention. See ¶¶ 0131-0134, 0584, 0630, 0632, and 1059-1069.
Conclusion
13. No claims allowed.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER J REDDIG whose telephone number is (571)272-9031. The examiner can normally be reached M-F 8:30-5:30 Eastern Time.
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, Greg Emch can be reached at 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PETER J REDDIG/Primary Examiner, Art Unit 1646
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