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/Restrictions
Applicant’s election of Group I, claims 7-8, 18-19, 21,24-25, 29-30, 38, 40-43, 45-46, and 53 and the species of SEQ ID NOs: 14-16, 8, 21, 22, 23, 25, 69, 66 and an isolated antigen binding protein in the reply filed on 2/10/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 38, 40-43, 45-46, 52, 55 and 56 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions and species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 2/10/2026.
Claims 7-8, 18-19, 21, 24-25, 29-30 and 53 are under consideration in the instant Office Action.
Information Disclosure Statement
The information disclosure statements filed 10/11/2023 fail to fully comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because no copies for foreign literature cited in the IDS were provided and the citations have therefore been lined through. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a). All references listed in the IDS that are not provided are lined through and not considered.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code, like www or http. See pages 1, 10, 19 and 39. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code (www). See MPEP § 608.01.
Claim Objections
Claim 21 is objected to because of the following informalities: “VH” is an acronym which stands for “heavy chain variable region” and needs to be spelled out in the claim, at least once in the first occurrence. 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.
Claims 7-8, 18-19, 21, 24-25, 29-30 and 53 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.
Instant claims 7-8, 18-19, 21, 24 and 29 recite the CDRs and heavy chain variable region sequences of the claimed antibody as “… an amino acid sequence as shown in…” It is unclear what is meant by “an amino acid sequence as shown in” as the use of “an amino acid” broadens the scope of the claim as it does not explicitly define all embodiments of the sequence. For example, this terminology of “an amino acid” can be interpreted as a subset of amino acids contained within the listed sequence identity number. Applicant is encouraged to amend the claim language to read as “…comprising SEQ ID NO:…” or “…comprising the amino acid sequence of SEQ ID NO:…” at every iteration to obviate this rejection. Dependent claims 25, 30 and 53 do not specifically have this language but depend from claims that suffer from this indefinite language and therefore, are also included in the indefiniteness rejection.
Further, independent claim 7 appears to only claim three of the six required CDRs that normally are required to describe a fully antibody. It is unclear if the claims are towards a normal antibody or a specific type of single domain antibody (sdAb) since the dependent claim 24 calls for a VHH. Therefore, it is unclear what type of antigen binding protein is being claimed in the independent claim.
MPEP § 2173.02 (II) states that one of the purposes of examination under 35 USC § 112, second paragraph is to determine whether the claim apprises one of ordinary skill in the art of its scope and, therefore, serves the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent. See, e.g., Solomon v. Kimberly-Clark Corp., 216 F.3d 1372, 1379, 55 USPQ2d 1279, 1283 (Fed. Cir. 2000). See also In re Larsen, No. 01-1092 (Fed. Cir. May 9, 2001) (unpublished). If the language of the claim is such that a person of ordinary skill in the art could not interpret the metes and bounds of the claim so as to understand how to avoid infringement, a rejection of the claim under 35 U.S.C. 112, second paragraph, would be appropriate. See Morton Int’l, Inc. v. Cardinal Chem. Co., 5 F.3d 1464, 1470, 28 USPQ2d 1190, 1195 (Fed. Cir. 1993). In this case, others are not fairly apprised of the scope of the claimed sequences for the claimed CDRs and heavy chains of the claimed antibodies and thus not fairly warned as to what constitutes infringement.
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.
Claims 7-8, 18-19, 21, 24-25, 29-30 and 53 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.
Independent claim 7 is directed to an isolated antigen binding protein with three CDRs with specific sequences, but still have written description issues because they rely on a pick and choose a sequence and leave the claim for interpretation of what is the instant sequence due to the “an amino acid” language, respectively, which allows unpredictable modification for the claimed CDRs. Further, the instant claims read on an antibody but fail to claim any CDRs for the light chain variable region of an antibody. Therefore, the claims read on only half of an antibody. Due to the vagueness of the instant claim language of what type of antibody is being claimed, a typical antibody that requires both a heavy and light chain variable region or a single-domain antibody, the written description issues are not clear but it is noted that either type of antibody still has written descriptions issues due to the fact of the potential language that allows for undisclosed modification in these very specific CDR regions of an antibody.
As such, these claims are directed to an antibody defined entirely by a variable structure with no specific function.
See MPEP §2163(I)(A) which states:
"The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art recognized correlation or relationship between the structure of the invention and its function. A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.”
In this case, antibodies generally share certain characteristics such as Fc regions or hinge regions. However, these structures are not correlated with the binding function of the antibody. The hyper variable regions (HVRs), i.e., complementarity determining regions (CDRs) of an antibody, are well established in the art as the portion of the binding region which imparts the specificity of an antibody. However, there is no way to a priori look at an antigen sequence and envisage the combination of six CDRs that will bind that antigen. First, even highly related CDRs may not bind the same target. See for example Kussie (instant PTO-892) who demonstrates that a single amino acid change in the heavy chain of an antibody which binds p-axophenylarsonate (Ars) completely abrogates the ability of the antibody to bind Ars but adds the functionality of binding the structurally related p-azophenylsulfonate (e.g., abstract). Second, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (p.7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on page 11).
See also Koenig 2017 (instant PTO-892), which provides a large mutation analysis study where every amino acid in both variable regions are substituted with every other amino acid. Looking at figure 1 of Koenig, the bottom half of each section (labeled VEGF) relates to the ability of the mutant to bind the original target, with blue meaning a reduced affinity and black meaning a complete loss of binding ability. In VH-CDR2, for example, mutating any given residue to cysteine, which is encompassed by the instant claims, resulted in reduced binding at 12 residues and a complete loss of binding at 5 residues. That is, at 100% of the positions, mutation to cysteine reduced or ablated the antibody’s ability to bind the target. Looking at a specific position, in 100% of the mutations of residue 55, binding was reduced (15/19) or eliminated (4/19). While residues 56-65 appear more tolerant of change, residues 50-55 are generally intolerant of change.
It is appreciated that Koenig is studying one specific antibody and there is no evidence that the instant antibodies would react in the same way. However, this is part of the problem. It is entirely unclear from the specification which residues of Applicant’s CDRs are tolerant or intolerant to change, and whether those tolerant positions are only tolerant to conservative mutations. The fact that some residues might tolerate mutation does not convey to the skilled artisan that Applicant knew which of the claimed residues were tolerant of such, i.e., does not convey that Applicant was in possession of those sequences which are mutated yet preserve the claimed function. In other words, the specification fails to convey possession of an invention commensurate in scope with what is now claimed and therefore fails to meet the written description requirement. Looking at Koenig figure 2A, ~200 mutations in the CDR region of the VH chain completely abrogates any binding. While 2B appears to indicate that the CDRs of VL are more tolerant of change than the heavy chain CDRs, still over half of the mutations reduce binding compared to the parent.
Thus, making changes to the CDR sequence of an antibody is a highly unpredictable process and the skilled artisan could not a priori make any predictions regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required functions.
The specification discloses multiple nanobodies or single domain antibodies with specific CDRs but the instant claims fail to make it clear that they are claiming single domain antibodies except for claim 24 which explicitly call for a VHH. However, as discussed above, without any way to determine how broad the genus of such nanobodies are, there is no way to determine if these nanobodies represent the full breadth of what is claimed. The disclosure of these specific nanobodies would not convey to the artisan that Applicant was in possession of the full genus of all nanobodies especially since there is no required structure/function requirement set forth in the instant claims. Therefore, the instant claims do not allow the skilled artisan to envisage the specific structure of such antibodies/nanobodies.
Further, it is well-known in the art that specificity of an antibody stems from the interaction of six CDRs and a nanobody is a single variable domain (VHH, aka single-domain antibody (sdAb)) only requiring the three CDRs from the one of the variable chain regions. Sufficient information must be provided to show that the inventor had possession of the invention as claimed. MPEP §2163(II)(A)(3)(a) also discusses Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004), where a method of using a PGHS-2 inhibitor did not meet the written description as the inhibitor itself was not sufficiently described, clearly indicating that written description of the compound is still required in a method of using that compound. In this case, it is clear from the specification that the invention comprises new antibodies, or at the least disclosure of new antibodies that could not have been envisaged from the prior art, which indicates that the prior art was not in possession of all the antibodies that attached solely via the binding of the affinity agent to the glutamate receptor as claimed.
In Williamson v. Citrix Online, LLC, 792 F.3d 1339, 1349, 115 USPQ2d 1105, 1111 (Fed. Cir. 2015) the court stated: “[t]he standard is whether the words of the claim are understood by persons of ordinary skill in the art to have a sufficiently definite meaning as the name for structure” (MPEP 2181). The ordinary artisan would not have understood that the applicant was in possession of only a finite number of antibodies and would not be able to envision the genera conjugates with an affinity agent that attached solely via the binding of the affinity agent to the glutamate receptor as claimed. Thus, the prior art cannot provide sufficient written description of this genus of compounds and the specification as filed does not sufficiently describe the genus either as there is an unknown amount of structurally distinct antibodies in this genus (see Amgen and Centocor decisions discussed above).
Thus, the art recognizes that the CDRs define the binding properties of an antibody and that even single amino acid changes to this region can completely abrogate the binding specificity of an antibody. As a further example, see Chen (instant PTO-892) which demonstrates single amino acid changes in the VH CDR2 sequence can increase binding, decrease binding, destroy binding, or have no effect on binding when compared to the wild-type antibody. Making changes to the CDR sequence of an antibody is a highly unpredictable process and the skilled artisan could not a priori make any predictions regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required functions.
One could not envisage which portions of the CDRs are necessary to impart the claimed binding properties or which could be interchanged without affecting such properties, nor does the instant specification provide guidance to this effect. As such, the disclosure of the instant antibodies does not convey possession of other antibodies with the same binding properties yet a different combination of six CDRs.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Vas-Cath, Inc., v. Mahurkar, 935 F.2d at 1563, 19 U.S.P.Q.2d at 1116. The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function. An antibody described only by modifiable CDRs, without any known or disclosed correlation between that function and the structure of the sequence, is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. In re Bell, 991 F.2d 781, 26 U.S.P.Q.2d 1529 (Fed. Cir. 1993). In re Deuel, 51 F.3d 1552, 34 U.S.P.Q.2d 1210 (Fed. Cir. 1995). In the instant case, the specification provides insufficient direction or guidance concerning the relationship between the structure of the possible antibody to demonstrate possession of the breadth of the genus of the antigen binding proteins encompassed by the instant claims, especially in view of the unpredictability of such an endeavor. The prior art as evidenced by Edwards et al., 2003 (instant PTO-892) teaches there is a substantially huge antibody diversity produced to one single antigen target. Edwards provides evidence that over 1000 antibodies, all different amino acid sequences, were generated towards one single protein antigen target (see abstract). Without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Without this guidance or direction the skilled artisan would not consider applicant to be in possession of the claimed genus of antibodies because the skilled artisan recognizes that even seemingly minor changes made without guidance or direction as to the relationship between the particular amino acid sequence of the instantly claimed antibody and its ability to bind antigen, can dramatically affect antigen-antibody binding.
Applicant has not described the claimed invention sufficiently to show they had possession of the claimed genus of the claimed antibody. The instant specification only discloses three specific nanobodies in their tables 1-3. 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 v. G.D. Searle & Co., 358 F.3d 916, 69 USPQ2d 1886 (Fed. Cir. 2004).
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, 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 claimed genus. 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.
What constitutes a "representative number" is an inverse function of the skill and knowledge in the art. Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the 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 species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus.
To provide adequate written description and evidence of possession of the claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In the instant case, the only factors present in the claims are a recitation of one generic, broad genus that encompassed a diverse and huge number of possible antibodies that bind the disclosed epitope. The specification does not provide a consistent structure for all of the possible antibodies and fails to provide a representative number of species for the claimed genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that they invented what is claimed.” (See Vas-Cath at page 1116).
With the exception of specifically disclosed nanobodies with specific CDRs as in the Tables 1-3 of the instant specification, the skilled artisan cannot envision the detailed chemical structure of all of the encompassed antibodies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Therefore, claims 7-8, 18-19, 21, 24-25, 29-30 and 53 do not meet the written description requirement.
Conclusion
No claims are allowed.
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/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675