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 .
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.
Priority
The present application was filed as a proper National Stage (371) entry of PCT Application No. PCT/FI2022/050616, filed 09/13/2022. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. 20215970, filed on 09/13/2022 in Finland.
Information Disclosure Statement
The information disclosure statements (IDS) filed 03/13/2024 and 03/31/3026 are considered, initialed and are attached hereto.
Claim Objections
Claim 15 is objected to because of the following informalities:
Claim 15 is objected to for abbreviations in the claims. It is suggested that abbreviations be accompanied at their first instance with the full term for the abbreviation, in the present case, the abbreviations are in reference to an depository accession numbers.
In the interest of clarity, it suggested that Applicant amend claim 15 in order to recite “A hybridoma cell line producing an anti-relaxin antibody, wherein the hybridoma cell line is selected from those cell lines deposited under China Center for Type Culture Collection (CCTCC) accession numbers: (i) C2021209, (ii) C2021210, or (iii) C2021211.”
Appropriate correction is required.
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.
Enablement
Claim 15 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The invention appears to employ a novel biological material, specifically monoclonal antibodies produced by hybridoma cell lines deposited under CCTCC accession numbers C2021209, C2021210, and C202211. Since the monoclonal antibodies are essential to practice the claimed invention, they must be readily available or obtainable by a repeatable method set forth in the specification, or otherwise readily available to the public. If the monoclonal antibodies are not so obtainable or available, the requirements of 35 U.S.C. 112(a) may be satisfied by a deposit of the hybridoma cell lines.
The specification does not disclose a repeatable process to obtain the monoclonal antibodies and it is not apparent if the biological material or source materials are both known and readily available to the public. The specification states that the hybridoma cell lines were deposited with the CCTCC (see originally filed specification at page 39). However, while it is indicated that the deposit is made under the conditions that satisfy the requirements of the Budapest Treaty, there is no indication of public availability.
An affidavit or declaration by Applicants, or a statement by an attorney of record over his or her signature and registration number, or someone empowered to make such a statement, stating that the instant invention will be irrevocably and without restriction released to the public upon issuance of a patent, would satisfy the deposit requirement made herein. In instances where the claimed invention consists of sexually unstable material, a deposit of the parental material is required if the parental material is considered sexually stable.
Written Description
Claims 1-14 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. See MPEP 2163.
Regarding claim 1, the claims encompass not only antibodies (referring to the capture, first detection and second detection antibodies) having the recited CDRs, but see also for the capture antibody, encompass “functional fragment” of the capture antibody recited, “which has independently at least 80% sequence identity, or at least 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to any one of SEQ ID NO: 7-12, wherein the functional fragment is capable of binding relaxin, in particular canine or feline relaxin, preferably canine relaxin”;
for the first detection antibody, encompass “functional fragment” of the first detection antibody, encompass “functional fragment… which has independently at least 80% sequence identity, or at least 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to any one of SEQ ID NO: 1-6, wherein the functional fragment is capable of binding relaxin, in particular canine or feline relaxin, preferably canine relaxin”;
for the second detection antibody, encompass “functional fragment” of the second detection antibody, encompass “functional fragment… which has independently at least 80% sequence identity, or at least 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to any one of SEQ ID NO: 13-18, wherein the functional fragment is capable of binding relaxin, in particular canine or feline relaxin, preferably canine relaxin”.
The claims are not only limited to the antibodies described by the specific recited 6 CDRs for each, but also a genus of antibodies, described merely by structural similarity to the claimed CDRs and by functional characteristic (capable of binding relaxin, in particular canine or feline, preferable canine). In terms of structural similarity, although the claims indicate a percentage of shared identity, the claims encompass unspecified sequence addition, deletion or substitution, the claims fails to specify which residue(s) can tolerate variation and which must be conserved in order to maintain functional ability.
Regarding Applicant’s actual reduction to practice, Applicant’s examples are much narrower in scope, the specification/examples discloses three specific monoclonal antibodies as species for each genus (antibodies having the specific CDR sequences recited, not functional fragments thereof), see specifically referring to mAbs 2H7, 2A4 and 9B8 (see examples starting at page 32) as antibodies which meet the structural and functional requirements of the claims.
Specifically, Applicant indicates 5 examples of antibodies initially produced in a first immunization (page 32), followed by another series of 9 produced in a second immunization (page 33), among which, Applicant reports 2H7 used as capture antibody as the species exhibiting desired results (page 34). See specifically (also page 34), Applicant reports only 2H7 capture antibody paired with 9B8 detection antibodies as the pair selected for use as it was the pair that did not show aggregation upon gold conjugation and showed high sensitivity for testing with dog. See also results reported page 37-38, 2H7-2A4/9B8 test was shown to function with whole blood samples, results were compared with commercial FASTest RELAXIn test, results were reported as more sensitive than commercial assay.
The level of skill in the relevant art is high. In particular, the methods for making and/or screening monoclonal antibodies (with particularly indicated desired binding properties) were well known in the art at the time of the invention. However, knowing how to produce/generate monoclonal antibodies does not support or provide evidence that Applicant is in possession of any and all possible species beyond those single disclosed species provided in Applicant’s actual reduction to practice (referring to those specifically produced antibodies as referenced in the examples, and specifically antibodies 2H7, 2A4 and 9B8 as in the present claims).
Amgen Inc. v. Sanofi further notes, pointing to Ariad Pharms., Inc. v. Eli Lilly & Co., 94 USPQ2d 1161 (Fed Cir. 2010):
To show invention, a patentee must convey in its disclosure that it “had possession of the claimed subject matter as of the filing date.” Id. at 1350. Demonstrating possession “requires a precise definition” of the invention. Id. To provide this “precise definition” for a claim to a genus, a patentee must disclose “a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Id.
Amgen at pages 7-8.
In this case, the disclosure of the specific individual monoclonal species is insufficient to represent the claimed genus recited in terms of identity to those specific species of monoclonal antibodies having the recited functional properties. There is substantial variability in the genus (as the application does not disclose which residues can tolerant variation and which must be conserved). Since there are a substantial variety of compounds possible within each of the claimed genus, without disclosure of any common partial structure or other sufficient identifying characteristics of the genus (for example, all 6 CDRs, OR the sequence for the heavy and light chain variable regions), the examples do not constitute a representative number of species and do not sufficiently describe the genus claimed.
It is not within the skill of the art to predict any and all substitutions that would result in products that retain the binding properties of a parent antibody. The art recognizes that structure (of a particular antigen to which an antibody/antibody fragment binds) is not necessarily a reliable indicator of function.
The teachings of Harlow et al. (Antibodies, A Laboratory Manual, Cold Spring Harbor laboratory, 1988, pages 25-26 and 37-59, cited herewith) which describe how the steps of the humoral immune response to an immunogen are dependent on APC, T-cell and B-cell recognition and processing of the immunogen in ways well known in the art to be highly unpredictable and heavily influenced by the particular immunogen and the specifics of the immunization protocol. Harlow et al. teach that even small changes in structure, such as loss of a single hydrogen bond, can profoundly affect antibody-antigen interaction (p. 25, last paragraph to page 26, second paragraph).
As an example to illustrate the potential scope of the genus of antibodies encompassed by the instant claims, consider the teachings of Meyer et al. (“New Insights in Type I and II CD20 Antibody Mechanisms-Of-Action With a Panel of Novel CD20 Antibodies”, British Journal of Haematology, 2018, 180, 808–820, |https://doi.org/10.1111/bjh.15132). Meyer describes the core binding region of the well-known anti-CD20 antibody rituximab corresponds to amino acid residues 170ANPS173, wherein N171 is the key residue for binding. By contrast, the OBZ and B1 anti-CD20 antibodies share an overlapping epitope with rituximab (170ANPSEKNSP178); however, in contrast to rituximab residues at positions 176–178 contribute the most to binding (see page 809, left col., 2nd full paragraph).
Meyer also described the production and characterization of a panel of new anti-CD20 antibodies which were shown to bind epitopes contained within or nearby the rituximab 170ANPS173 epitope but to bind to different residues than rituximab binds in this region (see page 811, “New CD20 mAbs with overlapping, but distinct epitopes,” see also page 815-16 bridging paragraph).
More particularly, Meyer teaches the newly created anti-CD20 mAbs m1 and m2 were found to bind within but also in the vicinity of the rituximab binding site (m1 and m2) and elsewhere (m2):
“detailed epitope mapping was performed for both mIgG2c-CD20 mAbs m1 and m2, by using PepScan technology. We identified the critical residues of m1 to be 168EPANPSEK175 by using linear (Figure S2A) and circular (Fig 2C, left) peptides with a positional amino acid scan covering the larger extracellular loop. Also, for m2, a signal decrease below the WT binding signal occurred within the 168EPANPSEK175 sequence motif but the binding signal to the linear (Figure S2B) and circular (Fig 2C, right) peptide was rather low. This suggests that the epitope of both mAbs is located on the larger loop in the same region, however their binding characteristics are different. The data suggests that m1 binds a linear epitope, whereas m2 binds to a conformational epitope.” (see ibid). While these antibodies bind within or nearby the rituximab 170ANPS173 epitope they do so with heavy and light chain CDRs non-homologous to those of rituximab.
The evidence supports that even if multiple antibodies bind epitopes within the same small region of a given polypeptide it is not uncommon for said antibodies to bind to different amino acids even within said small region and for said antibodies to have structurally dissimilar CDRs.
See also in support that there is unpredictability in the art, Brown et al. (“Tolerance of single, but not multiple, amino acid replacements in antibody VH CDR 2: a means of minimizing B cell wastage from somatic hypermutation?”, J Immunol. 1996 May;156(9):3285-91), describes how a one amino acid change in the VHCDR2 of a particular antibody was tolerated whereas, the antibody lost binding upon introduction of two amino changes in the same region (at 3290 and Tables 1 and 2).
In summary, without all 6 CDRs or the full sequence for the heavy and light chain variable regions, there is insufficient structure for binding with the claimed/required functional ability. As discussed in detail above, the prior art recognizes that polypeptides with even a single amino acid difference may have dramatically different biological activity, and further speaks to the unpredictability regarding antigen binding.
Regarding claim 2 is directed an antibody or a functional fragment thereof that is selected from i-iii, the functional fragment “has independently at least 80% sequence identity, or at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity” to those recited sequences at a-c, the functional fragment “capable of binding relaxin, in particular canine or feline relaxin, preferable canine relaxin”. The same analysis as applied above, also applies presently. The scope is even more broad however, because the claimed sequences are not longer limited to particular CDRs, but to the entire VH and VL region for each possible antibody, so the sequences is even larger regarding possible additions, substitutions and/or deletions. Notably regarding the language at the fragments “identity to any one of SEQ ID NO”.. also encompasses fragments having shared identity with only one of the indicated sequences (the other unspecified, as such casting an even wider scope regarding what is possibly encompassed in terms of structure).
Claim 3 appears somewhat more limiting, as 3 depends from claim 1 and claim 3 recites “wherein the functional fragments thereof is a functional fragment of any one of said anti-relaxin antibody (i), (ii) or (iii), which has 100% sequence identity to the VL and VH CDR1, CDR2 and CDR3 regions comprised therein, and which has independently at least 80% sequence identity, or at least 85%, 90%, 95%, 96%, 97%, 98% or 99% to any one of SEQ ID NO: 19, 20, 21, 22, 23 or 24 outside of said VL, and VH CDR1, CDR2 and CDR3 regions”; however, the same issues that arise with claim 1 arise at claim 3, because like with claim 1, claim 3 is not limited to the particular CDR sequences listed by the recited identifiers, but encompass possible variations (see above, claim 1 is not limited to the particular species as noted, i.e., 2H7, 2A4 and 9B8, but includes sequences with variations at one or more CDR for reach). The same analyses as above, applies presently (and similarly applies to claim 6, directed to a kit comprising the antibodies of claim 1, claim 7, comprising an anti-relaxin antibody”, see the language at claim 7 similar as addressed above at claim 1, and applies to claim 9).
Regarding claim 8, it is further noted regarding the encompassed species to each genus, “to any one of SEQ ID NO: 19, 20, 21, 22, 23 and 24” is language that further indicates the genus is so broad it further encompasses antibodies having the indicated functional ability and having structural identity to any one of those VH or VL domain sequences (not even specifying a combination of VH and VL domains). The analysis as indicated above for claim 1 similarly applies presently.
Regarding claims 11-14, these claims are directed to the nucleic acid encoding antibody for functional fragment thereof as recited in the previous claim 7 (claim 11), further vector or plasmid comprising the nucleic acid (claim 12), cell comprising the nucleic acid (claim 13), and method of preparing the antibody or functional fragment of claim 7, by culturing the cell (claim 14), however, as indicated, other than the specific species disclosed by Applicant, Applicant was not in possession of other antibody species encompassed by the claim meeting both the structural and functional requirements of the claims. As such, Applicant was similarly not in possession of the nucleic acid sequence encoding such antibodies.
For all of these reasons, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention.
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 1-14 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, 2, 5, 7 and 8 each recites “capable of binding relaxin, in particular canine or feline relaxin, preferably canine relaxin”, the language “in particular” and “preferable” is indefinite claim language. See MPEP 2173.05(d), regarding exemplary language, the language “in particular” and “preferable” is language that leads to confusion as to the scope of the claim, as it is not clear if the limitations that follow are particularly limiting or merely exemplary.
Claims 4 and 10 recite “wherein the functional fragment is a conservative sequence variant of any of the anti-relaxin antibodies”, the originally filed specification recites ““conservative sequence variant” as used herein, is intended to include nucleotide and amino acid sequence modifications, which do not significantly alter the binding properties of the anti-relaxin antibodies according to the present embodiments. Conservative nucleotide sequence variants include variants arising from the degeneration of the genetic code and from silent mutations.”. However, there is no indication what modifications are encompassed and tolerated (to still retain the functional ability required by the claims). As such, it is not readily clear what is an is not encompassed by those functional fragments that are “conservative sequence variants”; the boundaries of what sequences are and are not encompassed by the recited language are unclear, because one having ordinary skill cannot readily visualize or determine what modifications are included and retain binding.
Claim 14 recites the limitation "the cell in a medium" in 2. There is insufficient antecedent basis for this limitation in the claim. Claim 14 is recited as “a method of preparing the antibody or functional fragment according to claim 7”, the first step comprising “culturing the cell in a medium under conditions”, however claim 7 fails to recite or include any limitations specific to any cell having nucleic acid or vector or plasmid comprising the nucleic acid that would encode the antibody of claim 7.
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.
Claim 5 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 5 (depends from claim 1) recites “wherein the relaxin is canine or feline relaxin, preferable canine relaxin”, which the claims already recite this limitation in describing the claimed antibodies. 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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELLEN J MARCSISIN whose telephone number is (571)272-6001. The examiner can normally be reached M-F 8:00am-4:30pm.
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/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677
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