DETAILED ACTION
Status of Application, Amendments and/or Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The preliminary amendment of 10/27/23 has been entered in full. Claims 3-8, 10-12, 14-16, 18, 20, 24, 26, 29, 35-37, 41-53 and 55-58 are canceled. Claims 9, 13, 17, 19, 21-23, 25, 27-28, 38, 40 and 54 are amended. Claims 1-2, 9, 13, 17, 19, 21-23, 25, 27-28, 34, 38-40 and 54 are pending.
Specification
The disclosure is objected to because of the following informalities:
---The title of the invention is not descriptive because (1) it refers to “Notch4 Antibodies” but should properly refer to “Anti-Notch4 Antibodies”; e.g., see the specification at ¶ 4 on page 2 and (2), in part, it refers broadly to “Uses Thereof” of the antibodies but the claims are limited to methods of reducing Notch4 activity or treating disease associated with increased levels of Notch4. A new title is required that is clearly indicative of the invention to which the claims are directed. The following title is suggested: “Anti-Notch4 Antibody and Method of Reducing Notch4 Activity”.
---The disclosure contains an embedded hyperlink (browser-executable code) at ¶ 205 on page 56. Applicant is required to delete the embedded hyperlink; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01 (VII).
Appropriate correction is required.
Drawings
Corrected drawings in compliance with 37 CFR 1.121(d) are required because:
The instant drawings do not comply with 37 C.F.R. 1.84(U)(1), which states that partial views of a drawing which are intended to form one complete view, whether contained on one or several sheets, must be identified by the same number followed by a capital letter.
Figure 2M of the instant application, for example, is includes two figures on separate sheets labeled “FIG. 2M” and “FIG. 2M (CONTINATION)”. The second sheet should be renumbered “FIG. 2N”. In addition, each of Figures 3F, 5D, 10A and 11A should be corrected in the same manner.
Applicants are advised to employ the services of a competent patent draftsperson outside the Office, as the USPTO no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
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).
Applicants are reminded that once the drawings are changed to meet the separate numbering requirement of 37 C.F.R. 1.84(U)(1), Applicants are required to file an amendment to change the Brief Description of the Drawings and the rest of the specification accordingly.
Claim Objections
Claims 2, 22, 54 and 55 are objected to because of the following informalities:
In claim 2, lines 2-3, and claim 22, line 3, “antigen-binding” should be written “antigen binding” as in parent claim 1. Either format is acceptable but should be used consistently throughout the same set of claims.
Claim 54, as amended, begins “The method of any one of claim 38…”. The words “any one of” should be removed now the claim refers to a single parent claim.
The remaining claim(s) are objected to for depending from an objected claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 27, 28 and 40 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.
In claim 27, line 2, the recitation of “or composition thereof” is indefinite because it is unclear whether the “thereof” refers to the cell (line 1) or the antibody or antigen binding fragment (line 1) recited earlier in the claim.
Claim 40 recites the limitation “the disease or disorder associated with an increased level of Notch4” in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. Specifically, parent claim 38 recites “a disease or disorder associated with increased levels of Notch4”, and therefore the recitation in dependent claim 40 should match this wording for proper antecedent basis.
In claim 28, line 2, the recitation of “or composition thereof” is indefinite because it is unclear whether the “thereof” refers to the polynucleotide (line 1), nucleotide sequence (line 1) or antibody or antigen binding fragment (line 2) recited earlier in the claim.
Claim Rejections - 35 USC § 112(a), written description
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 1-2, 9, 13, 17, 19, 21-23, 25, 27-28, 34, 38-40 and 54 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.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112(a), it is necessary to understand what Applicants are claiming and what Applicants have possession of.
The claims are directed to products and methods related to an antibody, or antigen-binding fragment, that binds to the Notch4 protein. The broadest claim, independent claim 1, is directed to such an antibody, or fragment, that comprises one of four sets of variable region sequences defined by similarity to reference sequences. The first two sets are heavy chain variable region (VH) sequences; the first includes an amino acid sequence having at least 85% identity to SEQ ID NO: 2, 4 or 6; the second includes an animo acid sequence encoded by a nucleotide sequence having at least 85% identity a nucleotide sequence selected from the group of SEQ ID NO: 3, 5, or 7. The first second sets are light chain variable region (VL) sequences; the first includes an amino acid sequence having at least 85% identity to SEQ ID NO: 8, 10, 12 or 14; the second includes an animo acid sequence encoded by a nucleotide sequence having at least 85% identity a nucleotide sequence selected from the group of SEQ ID NO: 9, 11, 13 or 15. Claims 9 and 10 depend from claim 1 and limit the antibody to a set of 3 HCDRs (claim 9) or 3 LCDRs (claim 10) defined by similarity to reference sequences. The specification teaches that the reference sequences are from monoclonal antibody clones designated A1472 (SEQ ID NO: 2/8), A1527 (SEQ ID NO: 10) A1528 (SEQ ID NO: 4/12), and A1529 (SEQ ID NO: 6/14); see Tables 1 and 2 on pages 56-57.
Each claim is a genus claim because it encompasses an antibody, or antibody binding fragment, having the recited functional activity (binding to Notch4) and varying structural characteristics. The claims are not limited to a single structure, for example a monoclonal antibody having a single set of six complementarity-determining region (CDR) amino acid sequences, but instead encompass a variety of structures with the ability to bind Notch4. Independent claim 1 encompasses variability in two regards.
First, because claim 1 recites the four elements in the alternative, it is not limited to an antibody containing a single set of defined VH and VL amino acid sequences, but instead encompasses antibodies that have only a single defined chain; i.e., a defined VH or a defined VL sequence. Such encompasses antibodies that bind Notch4 in which the other chain has any possible amino acid sequence; e.g., an antibody comprising a VH having the amino acid sequence of SEQ ID NO: 2, 4 or 6 and a VL having any possible amino acid sequence; or an antibody comprising a VL having the amino acid sequence of 9, 11, 13, or 15 and a VH having any possible amino acid sequence.
Second, the heavy and light chain sequence of the antibody of claim 1 are not limited to those comprising an amino acid sequence that is the same as the reference sequence, but instead encompasses those that have 85% identity to the reference sequence. The VH sequences of SEQ ID NO: 2, 4 and 6 are 116, 119 and 112 amino acids in length, and thus sequences with at least 85% identity to these sequences encompass those with up to 17, 17, and 16 amino acid differences from the respective reference sequence. Likewise, the VL sequences of SEQ ID NO: 8, 10, 12 and 14 are 107, 107, 107 and 108 amino acids in length, and thus sequences with at least 85% identity to these sequences encompass those with up to 16 amino acid differences from the respective reference sequence. Furthermore, the sequence defined by reference to nucleotide sequences encompass even more variability. The sequences of SEQ ID NO: 3, 5 and 7 consist of 348, 357 and 336 nucleic acids, and thus sequences with at least 85% identity to these sequences encompass those with up to 52, 53, and 50 nucleic acid differences. Furthermore, as each nucleic acid difference can be in a different codon, this means that the encoded amino acid sequences (antibody sequences) encompass up to 52, 53 and 50 amino acid differences, which encompass changes in all of the heavy chain CDRs. The sequences of SEQ ID NO: 9, 11, 13 and 15 consist of 321, 321, 321 and 324 nucleic acids, and thus sequences with at least 85% identity to these sequences encompass those with up to 48 nucleic acid differences. Furthermore, as each nucleic acid difference can be in a different codon, this means that the encoded amino acid sequences (antibody sequences) encompass up to 48 amino acid differences, which encompass changes in all of the light chain CDRs.
Dependent claims 9 and 10 narrow either the heavy chain (claim 9) or light chain (claim 10) amino acid sequences of the claimed antibodies, but still encompasses any light chain sequence (claim 9) or any heavy chain sequence (claim 10). Furthermore, the heavy and light chain amino acid sequences of claims 9 and 10 are not limited to being identical to the defined reference CDR sequences, for examples SEQ ID NO: 16-18, but also include variants in which up to four amino acids are changed in each of the three CDRs, which is up to half of each CDR. For example, SEQ ID NO: 16-18 are 8, 8 and 9 amino acids, which means that 50%, 50% and 45% of each CDR can be changed.
The Federal Circuit in Amgen v. Sanofi, 872 F.3d 1367 (Fed. Circ. 2017) held that a claim directed to an antibody requires written description of the antibody itself rather than being satisfied solely by a written description of the antigen to which it binds (the so-called "newly characterized antigen" test). Thus, a description of the target protein (e.g. Notch4 protein) itself is not sufficient to provide a written description of the genus of antibodies binding to said target protein. Thus, in the instant case the specification must provide a written description of the structure of the claimed antibodies.
The prior art recognizes that antibodies bind to epitopes of 5-7 amino acids (Benjamini et al, 1991. Immunology: A Short Course, 2nd edition, page 40 only). While the general structure of an antibody was well-known in the prior art, it is the structure of the complementarity-determining regions (CDRs) that determines the specificity of a particular antibody, and said CDR structure is not predictable based on the epitope to which it binds. Thus, knowing the structure (CDRs) of one antibody does not allow the skilled artisan to predict the structure (CDRs) of other antibodies that bind to the same epitope or to the other epitopes in the same protein. This is evidenced by the exemplary antibodies recited in the claims, which each have a different set of CDR sequences, which are not predictable from each other. Furthermore, the relevant art, Ferrara et al (2015. mAbs. 7(1): 32-41) teaches that there is substantial variation in the structure of antibodies that bind to a single protein, on the order of hundreds of different sequences; specifically, see page 36: "The number of different HCDR3s selected against the test antigens ranges from 74 to 460 (Table 3), with the actual number of different antibodies likely to be significantly higher when different VL chains and additional VH mutations are taken into account” (pg 36).
While the disclosure of an antibody capable of binding to Notch4 and comprising a set of six specifically defined CDRs (3 HCDRs and 3 LCDRs) is sufficient to describe the antibody in and of itself, it is not sufficient to provide a description of the genus of antibodies encompassed by the instant claims, which encompass a genus of antibodies having less than a full complement of six defined CDRs. For example, the description of the HCDRs of SEQ ID NO: 16-18 and the LCDRs of SEQ ID NO: 19-21 does not provide a description of other CDRs that could be substituted for one or more of SEQ ID NO: 16-18 or SEQ ID NO: 19-21 and still produce an antibody capable of binding to Notch4, a large protein consisting of 2,003 amino acids. Even minor changes in the amino acid sequences of the heavy and light CDRs may dramatically affect antigen-binding function. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. The instant specification does not provide a description of other CDR sequences that can complement the recited CDR sequences and form a functional antibody. The recited functional limitation (Notch4 binding) is not sufficient to define the genus because it is only an indication of what the antibody does, rather than what sequences can be used and provide said functionality. The specification fails to disclose relevant identifying characteristics sufficient to describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize applicant was in possession of the claimed invention.
MPEP 2163 provides guidance for complying with the written description requirement of 35 U.S.C. 112(a) that the “specification shall contain a written description of the invention…”; this requirement is separate and distinct from the enablement requirement (Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010)). Written description for a claimed genus may be satisfied through sufficient description of a relevant number of species. This is dependent on whether one of skill in the art would recognize necessary common attributes or features possessed by the members of the genus. Generally, 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. Written description for a claimed genus can also be satisfied when relevant identifying characteristics are disclosed. Per MPEP 2163, “[d]etermine whether the specification discloses other relevant identifying characteristics sufficient to describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize applicant was in possession of the claimed invention. For example, if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function. Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function.” However, claiming by function does not necessarily satisfy the written description requirement. “[A] generic statement such as "vertebrate insulin cDNA" or "mammalian insulin cDNA," without more, is not an adequate written description of the genus because it does not distinguish the claimed genus from others, except by function. It does not specifically define any of the genes that fall within its definition. It does not define any structural features commonly possessed by members of the genus that distinguish them from others … 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. It is only a definition of a useful result rather than a definition of what achieves that result” (Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). Also, “[w]hen a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus" (Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005)), and “[A] sufficient description of a genus . . . requires the disclosure of either 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” (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69).
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states “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” (pg 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (pg 1116). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of antibody variants, 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 compound 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 (Fed. Cir. 1991). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 (BPAI 1993). In Fiddes, claims directed to mammalian FGFs were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, only:
(1) an antibody, or antigen-binding fragment, that binds to Notch4 and comprises:
(a) a heavy chain variable region (VH) comprising the HCDRs of SEQ ID NO: 16-18 and a light chain variable region (VL) comprising the LCDRs of SEQ ID NO: 19-21,
(b) a VH comprising the HCDRs of SEQ ID NO: 22-24 and a VL comprising the LCDRs of SEQ ID NO: 25-27,
(c) a VH comprising the HCDRs of SEQ ID NO: 28-30 and a VL comprising the LCDRs of SEQ ID NO: 31-33, or
(d) a VH comprising the HCDRs of SEQ ID NO: 34-36 and a VL comprising the LCDRs of SEQ ID NO: 37-39;
(2) a composition comprising (1);
(3) a cell comprising (1);
(4) a polynucleotide comprising a nucleotide sequence encoding (1);
(5) a method for reducing Notch4 activity, the method comprising administering (1) to a cell; or
(6) a method for reducing at least one symptom of a disease or disorder associated with increased levels of Notch4, the method comprising administering a therapeutically effective amount of (1) to a subject in need thereof;
but not the full breadth of the claims meets the written description provision of 35 U.S.C. §112(a). Applicants are reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (pg 1115).
Note
No prior art has been identified that teaches or suggests an antibody, or antigen-binding fragment, that binds to Notch4 and comprises:
(a) a heavy chain variable region (VH) comprising the HCDRs of SEQ ID NO: 16-18 and a light chain variable region (VL) comprising the LCDRs of SEQ ID NO: 19-21;
(b) a VH comprising the HCDRs of SEQ ID NO: 22-24 and a VL comprising the LCDRs of SEQ ID NO: 25-27;
(d) a VH comprising the HCDRs of SEQ ID NO: 28-30 and a VL comprising the LCDRs of SEQ ID NO: 31-33; or
(d) a VH comprising the HCDRs of SEQ ID NO: 34-36 and a VL comprising the LCDRs of SEQ ID NO: 37-39.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY C HOWARD whose telephone number is (571)272-2877. The examiner can normally be reached on Monday to Friday from 9 AM to 5 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford, can be reached at telephone number (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ZACHARY C HOWARD/Primary Examiner, Art Unit 1674