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 without traverse of Group I in the reply filed on June 18, 2026 is acknowledged.
Claims 1-6, 8-9, 15-18, 20-21, 23-24, and new claims 29-30 are pending. Claims 7, 10-14, 19, 22, 25-28 are canceled. Claims 15-17, 20-21, 23-24, 30 are withdrawn. Claims 1-6, 8-9, 18, 29 are examined.
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.
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 1-3, 5-6, 8-9, 18, 29 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for an antibody that bind MYH9 and comprising sequence of SEQ ID NO: identified for all six complementarity determining regions (CDRs) from both heavy and light chain variable regions, does not reasonably provide enablement for a antibody comprising CDR with 70% percent identity to whole antibody, or antibody with less than 6 complementarity determining regions (CDRs) from both heavy and light chain variable regions. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The first paragraph of § 112 requires that the patent specification enable "those skilled in the art how to make and use the full scope of the claimed invention without `undue experimentation."' Genentech, Inc. v. Novo Nordisk AIS, 108 F.3d 1361, 1365, 42 USPQ2d 1001, 1004 (Fed. Cir. 1997) (quoting In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)); see also In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). ("[T]he scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art."). Whether making and using the invention would have required undue experimentation, and thus whether the disclosure is enabling is a legal conclusion based upon several underlying factual inquiries. See In re Wands, 858 F.2d 731, 735, 736-37, 8 USPQ2d 1400, 1402, 1404 (Fed. Cir. 1988). As set forth in Wands, the factors to be considered in determining whether a claimed invention is enabled throughout its scope without undue experimentation include the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art, and the breadth of the claims.
Likewise, in Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991), the court affirmed the holding of invalidity of claims to analogs of the EPO gene under § 112 for lack of enablement where applicants had claimed every possible analog of the EPO gene but had disclosed only how to make EPO and a very few analogs. "[D]espite extensive statements in the specification concerning all analogs of the EPO gene that can be made, there is little enabling disclosure of the particular analogs and how to make them .... There may be many other genetic sequences that code for EPO-type products. Amgen has told how to make and use only a few of them and is therefore not entitled to claim all of them." Id., 927 F.2d at 1213-14, 18 USPQ2d at 1027.
Claims encompass a generic antibody which bind MYH9 and which are varying fragment size with less than the 6 CDRs of the variable domains. Claims encompass an antibody variants and fragments because the antibody are claimed with 70% sequence identity to the SEQ ID NO: of light or heavy chain. The claims read on variant antibody with deletion, addition or mutation to other frame regions or regions which affect CDR region which causes the antibody to not function. It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, Fundamental Immunology, 3rd Edition, 1993, pp. 292-295, under the heading "Fv Structure and Diversity in Three Dimensions"). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of a given antibody. 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 the required conformation of the CDRs are required in order to produce a protein having antigen-binding function; and further, that proper association of heavy and light chain variable regions is required in order to form functional binding sites (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30). The claims read on variant antibody with deletion, addition or mutation to other frame regions or regions which affect CDR region which causes the antibody to not function. The genus of antibodies as claimed includes variations in the polypeptide which affect CDRs function as antibodies. Mutation of even a single amino acid residue affects antigen binding. Wu, et al. (Journal of Molecular Biology, 1999. Vol. 294, pages 151-162,) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left column) but certain residues have been identified as important for maintaining conformation. Additionally, even minor changes in the amino acid sequences of the heavy and light variable regions, including framework, may dramatically affect antigen-binding function as evidenced by MacCallum, et al. (Journal of Molecular Biology, 1996. Vol. 262, pages 732-745) who analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right column) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left column). The specification does not enable an antibody with changes to framework which have the claimed functional characteristics.
Bendig M. M. (Methods: A Companion to Methods in Enzymology, 1995; 8:83-93) reviews that the general strategy for "humanizing" antibodies involves the substitution of all six CDRs from a rodent antibody that binds an antigen of interest, and that all six CDRs are involved in antigen binding (see entire document, but especially Figures 1-3). Similarly, the skilled artisan recognized a "chimeric" antibody to be an antibody in which both the heavy chain variable region (which comprises the three heavy chain CDRs) and the light chain variable region (which comprises the three light chain CDRs) of a rodent antibody are recombined with constant region sequences from a human antibody of a desired isotype (see entire document, but especially Figures 1-3).
MacCallum et al. (J. Mol. Biol. (1996) 262:732-745), analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right col) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.). The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al. (2003) BBRC 307, 198-205, which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left col.). Thus, while one can make the statement that CDRs from a single antibody chain make a significant contribution in the antigen binding, the CDR domains from a single chain are not the only residues that influence binding, and in fact the prior art does not support that CDR domains from a single chain alone are sufficient to define the binding specificity of an antibody.
Due to the large quantity of experimentation necessary to determine which antibodies comprising less than the full complement of CDRs would bind the antigen, the lack of direction/guidance presented in the specification regarding same, the absence of sufficient working examples directed to same, the complex nature of the invention, the state of the prior art establishing that formation of an intact antigen binding site of antibodies routinely requires the association of the complete heavy and light chain variable regions each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope, and the breadth of the claims which fail to recite the requirement for a full complement of 6 CDRs, undue experimentation would be required of the skilled artisan to make and/or use the claimed invention in its full scope.
Therefore, based on the above Wands analysis, a preponderance of the evidence supports a conclusion that one skilled in the art would not have been enabled to make and use the invention of claims without undue experimentation.
Claims 1-3, 5-6, 8-9, 18, 29 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. This is a written description requirement.
Claims encompass a generic antibody which bind MYH9 and which are varying fragment size with less than the 6 CDRs of the variable domains. Claims encompass an antibody variants and fragments because the antibody are claimed with 70% sequence identity to the SEQ ID NO: of light or heavy chain. The claims read on variant antibody with deletion, addition or mutation to other frame regions or regions which affect CDR region which causes the antibody to not function. However, such antibody structure cannot be envisioned which function with binding specifically as disclosed in the specification. As written, the claims read on any immunoglobulin protein variant that comprises changes in the frame sequence without defined boundaries. As written, the claims read on variant antibody with deletion, addition or mutation to other frame regions or regions which affect CDR region which causes the antibody to not function. The genus of antibodies as claimed includes variations in the polypeptide which affect CDRs function as antibodies. Mutation of even a single amino acid residue affects antigen binding. Wu, et al. (Journal of Molecular Biology, 1999. Vol. 294, pages 151-162,) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left column) but certain residues have been identified as important for maintaining conformation. Additionally, even minor changes in the amino acid sequences of the heavy and light variable regions, including framework, may dramatically affect antigen-binding function as evidenced by MacCallum, et al. (Journal of Molecular Biology, 1996. Vol. 262, pages 732-745) who analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right column) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left column). The specification does not disclose an antibody with changes to framework which have the claimed functional characteristics. Thus, applicant was not in possession of the broad genus of antibodies as claimed.
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. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d. Additionally, “a patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.” Noelle v. Lederman, 355 F.3d 1343, 1350 (Fed. Cir. 2004).
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 disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004). ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)(Claims directed to PTFE dental floss with a friction-enhancing coating were not supported by a disclosure of a microcrystalline wax coating where there was no evidence in the disclosure or anywhere else in the record showing applicant conveyed that any other coating was suitable for a PTFE dental floss.).
The specification discloses specific antibody including the antibody that binds to MYH9 and comprising the sequences of SEQ ID NO: for all 6 CDRs and heavy and light chain. Claims encompass antibody with a single CDR or a single CDR which is defined by SEQ ID NO:. Furthermore, the claims encompass CDR3 which contain multiple variants. However, the specification does not provide sufficient written description as to the structural features of the claimed genus of antibodies and the correlation between the chemical structure and function of the genus of antibodies, such as residues that are essential for antigen binding. The specification does not provide teaching of a single CDR antibody. One skilled in the art does not teach a single CDR antibody. Furthermore, while the specification teach individual mutations in the CDR but does not teach the multiple changes in the CDR. One skilled in the has not shown the correlation between taking individual changes in the CDRs and combining the mutations in the CDR.
It has been well known that minor structural differences even among structurally related compounds can result in substantially different biology, expression and activities. Based on the instant disclosure one of skill in the art would not know which residues are essential, which residues are non-essential and what particular sequence lengths identify essential sequences for identifying an antibody that binds to EP4 and encompassed by the claimed specificity of function. Mere idea of function is insufficient for written description; isolation and characterization at a minimum are required.
Skolnick, et al. (Trends in Biotechnology, 2000. Vol. 18, pages 34-39) teach that the skilled artisan is well aware that assigning functional activities for any particular protein or protein family based on sequence homology is inaccurate, in part because of the multifunctional nature of proteins (e.g., “Abstract” and “Sequence-based approaches to function prediction”, page 34). Even in situations where there is some confidence of a similar overall structure between two proteins, only experimental research can confirm the artisan’s best guess as to function of the structurally related protein (see in particular “Abstract” and Box 2).
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. 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. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs but also framework region, may dramatically affect antigen-binding function as evidenced by MacCallum, et al. (Journal of Molecular Biology, 1996. Vol. 262, pages 732-745) who analyzed many different antibodies for interactions with antigen and state that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts (see page 733, right column) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left column).
The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site is underscored by Casset, et al. (Biochemical and Biophysical Research Communications, 2003. Vol. 307, pages 198-205) which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (see entire document). Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left column) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left column). Vajdos, et al. (Journal of Molecular Biology, 2002. Vol. 320, pages 415-428) additionally state that antigen binding is primarily mediated by the CDRs more highly conserved framework segments which connect the CDRs are mainly involved in supporting the CDR loop conformations and in some cases framework residues also contact antigen (page 416, left column). Wu, et al. (Journal of Molecular Biology, 1999. Vol. 294, pages 151-162) state that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left column) but certain residues have been identified as important for maintaining conformation.
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. See, e.g., Eli Lilly. Description of a representative number of species does not require the description to be of such specificity that it would provide individual support for each species that the genus embraces. If a representative number of adequately described species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112, first paragraph.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, 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.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of polypeptides, 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.
One cannot describe what one has not conceived. See Fiddles v.Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Therefore, antibodies comprising SEQ ID NO: with 6 CDRs but have undefined framework mutations, antibody with single CDR, or an antibody comprising multiple mutations in the CDR does not meet the written description provision of 35 U.S.C. § 112, first paragraph. 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).
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 6, is/are rejected under 35 U.S.C. 102a1 as being anticipated by Schramek et al.(US 2015/0148411).
Schramek disclose antibody which binds MYH9 (paragraph 5). Schramek disclose Dog MYH9 (para 33).
No claims are allowed.
Claim 4 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL D PAK whose telephone number is (571)272-0879. The examiner can normally be reached on flexible time.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford can be reached on 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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/MICHAEL D PAK/Primary Examiner, Art Unit 1674
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