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 .
Election/Restriction:
Applicant's election without traverse of Group I (claims 57-70; species of antibody: CDRH1/CDRH2/CDRH3 and VH sequence recited of SEQ ID NOs: 4/16/20 and SEQ ID NO:72, respectively), filed on 1/23/2026 is acknowledged.
Amended claims 57-70, (1/23/2026), are under consideration by the Examiner.
Claims are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claims 1-56 have been canceled.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on 12/20/2024 is in compliance with the provisions of 37 CFR 1.97 and has been considered by the examiner.
Applicant is reminded of their duty to disclose to the Office all information known to the person to be material to patentability as defined in 37 CFR 1.56. As stated therein, “[e]ach individual associated with the filing and prosecution of a patent application has a duty of candor and good faith in dealing with the Office, which includes a duty to disclose to the Office all information known to that individual to be material to patentability as defined in this section”.
Claim Rejections - 35 USC § 112(b)
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.
4a. Claims 57-70 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 pre-AIA the applicant regards as the invention.
Claim 57, line 1, is vague and indefinite because it recites “a heavy chain antibody that binds to Folate Receptor (FOLR1)…” which is confusing. The specification on page 2, [005] recites:
“It is known, however, that sera of camelids (sub-order Tylopoda which includes camels,
dromedaries and llamas) contain a major type of antibodies composed solely of paired H-chains (heavy-chain only antibodies or UniAbsTM). The UniAbsTM of Camelidae (Camelus dromedarius, Camelus bactrianus, Lama glama, Lama guanaco, Lama alpaca and Lama vicugna) have a unique structure consisting of a single variable domain (VHH), a hinge region and two constant domains (CH2 and CH3), which are highly homologous to the CH2 and CH3 domains of classical antibodies. These UniAbsTM lack the first domain of the constant region (CHI) which is present in the genome, but is spliced out during mRNA processing. The absence of the CHI domain explains the absence of the light chain in the UniAbsTM, since this domain is the anchoring place for the constant domain of the light chain. Such UniAbsTM naturally evolved to confer antigen-binding specificity and high affinity by three CDRs from conventional antibodies or fragments thereof.”
It is suggested that the preamble of the claim be amended to recite “a single variable domain (VHH) antibody comprising a heavy chain that binds to Folate Receptor (FOLR1)…” for clarity.
Claims 58-70 are rejected as vague and indefinite for the recitation of “heavy chain antibody…” for the reasons set forth above with respect to independent claim 57.
Claim Rejections - 35 USC § 112(a), written description
5. 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.
5a. Claims 57-70 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant has claimed a heavy chain antibody that binds to Folate Receptor Alpha (FOLR1), comprising a first heavy chain variable region comprising:(a) a CDR1 sequence selected from the group consisting of SEQ ID NOs: 1-5; (b) a CDR2 sequence selected from the group consisting of SEQ ID NOs: 6-17; and (c) a CDR3 sequence selected from the group consisting of SEQ ID NOs: 18-22, however Applicant has not provided description of a single variable domain antibody with mixing and matching of (a) CDR1 selected from SEQ ID NOs: 1-5; (b) CDR2 selected from SEQ ID NOs: 6-17; and (c) CDR3 selected from SEQ ID NOs: 18-22.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. § 112(a), "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, 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 genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3).
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), the following is noted.
To show invention, a patentee must convey in its disclosure that it “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, a patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen at page 1358).
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted: “A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “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.” Id. at 1566, 43 USPQ2d at 1404 (quoting Fiers. 984 F.2d at 1171, 25 USPQ2d at 1606). Also see Enzo-Biochem v. Gen-Probe 01-1230 (CAFC 2002).
As discussed above, Applicant has claimed a heavy chain antibody that binds to Folate Receptor Alpha (FOLR1), comprising a first heavy chain variable region comprising:(a) a CDR1 sequence selected from the group consisting of SEQ ID NOs: 1-5; (b) a CDR2 sequence selected from the group consisting of SEQ ID NOs: 6-17; and (c) a CDR3 sequence selected from the group consisting of SEQ ID NOs: 18-22. Recent court cases have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See for example AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) as well as Amgen v. Sanofi. (Fed Cir, 2017-1480. 10/5/2017). Indeed, in Amgen the court indicates that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e. the antigen, as knowledge of the chemical structure of an antigen does not give the required kind of structure-identifying information about the corresponding antibodies, with the antibody-antigen relationship be analogized as a search for a key on a ring with a million keys on it.
Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361).
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
In the instant case, the specification discloses specific anti-FOLR1 antibodies set forth in Tables 1-9, pages 26-34, [0147]-[0155]. Applicant has not disclosed the various mixing and matching of CDR1 (SEQ ID NOs: 1-5), CDR2 (SEQ ID NO:6-17), and CDR3 (SEQ ID NO:18-22) to obtain a single variable domain antibody that binds to FOLR1. Applicant is reminded that the courts have long ruled that “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” See University of Rochester. 358 F.3d at 927, 69 USPQ2d at 1895. As such, disclosure of a screening assay to test for functional properties of an antibody does not provide evidence of possession of the antibody itself.
It is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, CDR2 and CDR3, which provide the majority of the contact residues for the binding of the antibody to its target epitope (in this specific case the three CDRs for the single variable domain antibody (VHH) See specification, [0093]-[0094], pages 14-15) .
“The terms "heavy chain-only antibody," and "heavy chain antibody" are used interchangeably herein and refer, in the broadest sense, to antibodies, or more or more portions of an antibody, e.g., one or more arms of an antibody, lacking the light chain of a conventional antibody. The terms specifically include, without limitation, homodimeric antibodies comprising the VH antigen-binding domain and the CH2 and CH3 constant domains, in the absence of the CH1 domain; functional (antigen-binding) variants of such antibodies, soluble VH variants, Ig-NAR comprising a homodimer of one variable domain (V-NAR) and five C-like constant domains (C-NAR) and functional fragments thereof; and soluble single domain antibodies (sUniDabsTM). In one embodiment, a heavy chain-only antibody is composed of a variable region antigen-binding domain composed of framework 1, CDR1, framework 2, CDR2, framework 3, CDR3, and framework 4. In another embodiment, a heavy chain-only antibody is composed of an antigen-binding domain, at least part of a hinge region and CH2 and CH3 domains.
In another embodiment, a heavy chain-only antibody is composed of an antigen-binding domain, at least part of a hinge region and a CH2 domain. In a further embodiment, a heavy chain-only antibody is composed of an antigen-binding domain, at least part of a hinge region and a CH3 domain. Heavy chain-only antibodies in which the CH2 and/or CH3 domain is truncated are also included herein. In a further embodiment, a heavy chain is composed of an antigen binding domain, and at least one CH (CH1, CH2, CH3, or CH4) domain but no hinge region. The heavy chain-only antibody can be in the form of a dimer, in which two heavy chains are disulfide bonded or otherwise, covalently or non- covalently, attached with each other. The heavy chain-only antibody may belong to the IgG subclass, but antibodies belonging to other subclasses, such as IgM, IgA, IgD and IgE subclass, are also included herein. In a particular embodiment, a heavy chain antibody is of the IgG1, IgG2, IgG3, or IgG4 subtype, in particular the IgG1 or IgG4 subtype. In one embodiment, a heavy-chain antibody is of the IgG4 subtype, wherein one or more of the CH domains is modified to alter an effector function of the antibody.
In one embodiment, the heavy-chain antibody is of the IgG1 or IgG4 subtype, wherein one or more of the CH domains is modified to alter an effector function of the antibody. Modifications of CH domains that alter effector function are further described herein. Non-limiting examples of heavy-chain antibodies are described, for example, in WO2018/039180, the disclosure of which is incorporated herein by reference in its entirety.
In some embodiments, the heavy chain-only antibodies herein are used as a binding (targeting) domain of a chimeric antigen receptor (CAR). The definition specifically includes human heavy chain-only antibodies produced by human immunoglobulin transgenic rats (UniRatTM), called UniAbsTM. The variable regions (VH) of UniAbsTM are called UniDabsTM, and are versatile building blocks that can be linked to Fc regions or serum albumin for the development of novel therapeutics with multi-specificity, increased potency and extended half-life. Since the homodimeric UniAbsTM lack a light chain and thus a VL domain, the antigen is recognized by one single domain, i.e., the variable domain of the heavy chain of a heavy-chain antibody (VH or VHH).”
The amino acid sequences and conformations of the heavy chain CDRs (in this application) are critical in maintaining the antigen binding specificity and affinity which is characteristic of single variable domain (VHH) comprising a heavy chain. It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al., 1982, see entire document, particularly the abstract and the middle of the left column of page 1982). However, as discussed above, only the single variable domain antibodies (VHH) in Tables 1-9, pages 26-34, [0147]-[0155] have been described.
Indeed, in AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) the court ruled that all of the antibodies disclosed by AbbVie were all structurally similar as they were variants of a starting antibody named Joe9 and therefore did not serve to inform artisans as to the breadth of structures which had the recited function of cytokine binding. In the instant application, the instant claims recite antibodies to be used in the claimed methods while the specification does not disclose structures which necessarily have the requisite functions. The instant specification fails to disclose sufficient structural information to indicate to artisans that Applicant had possession of the various antibodies as presently claimed. Therefore, it appears that the broad genus of antibodies recited in Applicant’s claims lacks adequate written description because there does not appear to be sufficient correlation between the structure of the antibodies in question and their recited functional activities. As such a skilled artisan would reasonably conclude that Applicant was not in possession of the recited genus of antibodies. Therefore, there is insufficient written description for genus of antigen-binding immunoglobulin molecules having the claimed “limitations” at the time the invention was made and as disclosed in the specification as filed under the written description provision of 35 USC 112.
Appellant has been reminded that Vas-Cath makes clear that the written description provision of 35 USC 112 is severable from its enablement provision. (See page 1115.)
Conclusion
Claims 57-70 are rejected.
No claim is allowed.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PREMA MARIA MERTZ whose telephone number is (571)272-0876. The examiner can normally be reached on Monday to Thursday from 7:30am to 6:00pm.
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/PREMA M MERTZ/ Primary Examiner, Art Unit 1674
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