Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Amendment filed July 29, 2025 is entered.
Claims 1-15, 20 and new claims 21-22 are pending. Claims 20-22 are withdrawn. Claims 16-19 are canceled. Claims 1-15 are examined.
Newly submitted claims 21-22 are directed to an invention that is independent or distinct from the invention originally claimed for the following reasons:
IV. Claims 21-22, drawn to a complex comprising muscarinic receptor M2 and means for specifically binding the muscarinic receptor M2, classified C07K 14/705.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 21-22 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
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.
Claims 1-15 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 VHH antibody which have variant CDRs because of of percent identity claimed to the CDR sequences. Although claims have been amended to polypeptide instead of a variable domain of a heavy chain only antibody, the polypeptide encompass variable domain of a heavy chain only antibody because of the same claim limitation in the body of the claims. Claims encompass antibody variants because the antibody are claimed with precent sequence identity to the SEQ ID NO: of the VHH. The claims read on variant antibody with deletion, addition or mutation to CDRs and 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 CDRs and 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 many nanobodies including the nanobody that binds to M2 muscarinic receptor and comprising the sequences of SEQ ID NO: for all CDRs of VHH. The specification does not provide sufficient written description as to the structural features of the claimed genus of antibodies and the correlation between the structure and function of the genus of antibodies, such as residues that are essential for antigen binding.
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.
Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341 (Fed. Cir. 2011) and AbbVie Deutschland GmbH v. Janssen Biotechnology, Ltd. 759 F.3d 1285 (Fed. Cir. 2014) provide holding against generic claims to antibodies whose structure cannot be envisioned from the specific species of structure provided. Claims encompass antibodies whose structure cannot be envisioned because claims encompass an antibody that binds to an LGR7 protein and which competes for binding with any one of the antibody with the specific antibody with the CDRs comprising a specific SEQ ID NO: with or without the functional limitation of various percentage of blocking (20%, 30% and 50%). Antibodies claimed encompass unlimited changed to the structure of antibody disclosed SEQ ID NO: because the antibodies only require the competition with the known antibody. The genus of antibodies as claimed includes variations in the entire polypeptide. AbbVie [AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 111 USPQ2d 1780, at 1788 (Fed. Cir. 2014)] held (at 1790) that, “Although the number of the described
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appears high quantitatively, the described
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are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the
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genus See Ariad, 598 F.3d at 1351 (“[No] bright-line rules govern[] the number of
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that must be disclosed to describe a
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genus claim, as this number necessarily changes with each invention, and it changes with progress in a field.”).
Therefore, antibodies comprising SEQ ID NO: with 6 CDRs but have undefined framework or CDR mutations 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).
Applicants argue that no specificity or function was recited in the amended claims and thus cannot be held to lack written description. However, the polypeptide comprising the claimed structure has a function including the VHH function of the CDRs claimed. The generic term “polypeptide” encompass the term VHH and its function.
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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.
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