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 .
DETAILED ACTION
Response to Amendment and Arguments
The Amendment filed on 2/5/2026 in response to the previous Non-Final Office Action (11/5/2025) is acknowledged and has been entered.
Claims 1-41 have been cancelled.
Claims 62-65 have been added.
Claims 42-65 are pending.
Claims 42-65 are pending and examined for a polynucleotide encoding an antibody comprising a heavy chain VH sequence SEQ ID NO: 234 comprising CDR-H1-3 having the sequences of SEQ ID NOs: 147, 153 and 156 and/or Light chain sequence SEQ ID NO: 235 comprising CDR-L1-3 having the sequences of SEQ ID NO: 159, 172 and 195 respectively, which binds to human MuSK on merits.
The following office action contains NEW GROUNDS of rejection-based on the amendment.
Rejection Maintained and Response to Arguments
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.
Written Description:
Mixed and Matched VH and VL encoding by polynucleotides, and
Antibody contains only VH or VL domain without a full set of six CDRs.
Claims 42, 44, 47-52, 54, and 57-61 remain 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.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Possession may be shown. For claimed product the specification must provide sufficient distinguishing identifying characteristics of the genus, including disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, level of skill and knowledge in the art, and predictability in the art or any combination thereof.
The claims are broadly drawn to
An isolated polynucleotide encoding a heavy chain variable region (VH) and a light chain variable region (VL) of an antibody that specifically binds to human muscle-specific tyrosine-protein kinase (MuSK), wherein:
(a) the VH comprises a CDR-H1, a CDR-H2, and a CDR-H3 of the VH amino acid sequence of SEQ ID NO: 97, 99…….. 234, 236,…and
(b) the VL comprises a CDR-L1, a CDR-L2, and a CDR-L3 of the VL amino acid sequence of SEQ ID NO: 98, 100,………..235, 237,…..
The amended claim 42 comprises VH and VL domain, but depended claim 44 still recites VH or VL domain.
The amended claim 42 and dependent claims still recite Mixed and Matched VH and VL.
Thus, the claimed antibody encoded by a polynucleotide includes:
1) a genus of antibodies with Mixed and Matched VH and VL, in which any listed VH could be paired to any VL listed in the claims,
2) the claimed antibody comprises merely one VH or one VL domain that contains only 3 CDRs, not full set of 6 CDRs.
The specification first teaches that MuSK is a receptor tyrosine kinase expressed in skeletal muscle and has a crucial and master role in forming and maintaining neuromuscular synapse [0087-0091]. The specification teaches MuSK antibody-based Molecules binding to MuSK protein or epitopes within the protein, wherein the antibodies are full length antibody or antigen binding fragment comprising a VH and a VL [0098]+. The specification lists numbers of antibodies, antigen-binding domain binding to and activating human MuSK, wherein the antibodies or the binding domains comprising full set of six CDRs from VHs and from VLs (tables 1 and 2) including elected antibody with CDR-H1-3 having the sequences of SEQ ID NOs: 147, 153 and 156 and CDR-L1-3 having the sequences of SEQ ID NOs: 159, 172 and 195 ([0127-[0183], [0179] in particular), that corresponds to the VH and VL domains comprising the sequences of SEQ ID NO: 234 and 235 (antibody 3B2gm1, table 3).
The examples of the specification teach that amino acid substitutions for the IgG1 antibody and binding to the antigen MuSK from different species are tested and anti-human MuSK antigen binding antibodies are obtained, which comprise VH and VL domains comprising the sequences of SEQ ID NO: 234 and 235 respectively (table 10, 3B2gm1).
The specification although contemplates the antibody fragment with only VH or VL domain [099], there is no reduced practice for testing the function and activity to MuSK described in the application.
The specification provides no proper description for the claimed antibody with Mixed and Matched VH and VL and there is no correlation between the structure of the antibodies and their claimed function, MuSK binding. It is well known, the CDRs in VL and VH are the critical amino acids for the antigen recognition and affinity of binding, one amino acid change within the CDRs or own CDR switch could result in antibody having different affinity or even binding to totally different antigens as compared to the parent antibody. While the claims, as written, require alternations of entire 3 CDRs in VH paired to different VL or vice versa, one skilled in the art would know how to match VH and VL to obtain an antibody that can bind to the claimed antigen MuSK without reducing to practice or quantities of experimentations.
It is well known, the CDRs, VL/VH and scFv contain the critical amino acids for the antigen recognition and affinity of binding, even one amino acid change within the CDRs could result in antibody having different affinity or even binding to totally different antigens as compared to the parent antibody. When VHCDR sequences are Mixed and Matched, the CDR1, CDR2 and/or CDR3 sequence from a particular VH sequence is replaced with a structurally similar but different CDR sequence(s). Thus, it will be readily apparent to the ordinarily skilled artisan that novel VH and VL sequences are created by substituting one or more VHCDR and/or VLCDR region sequences with structurally similar but different sequences from the CDR sequences for the antibodies as claimed. While the claims, as written, require alternations (variation) the amino acids in CDRs, or VH/VL or scFv. One skilled in the art would not know how to match the amino acids used for MuSK protein binding without undue quadrative experimentations.
Therefore, only the polynucleotide encoding the antibody binding to human MuSK with a pair of VH/VL comprising the sequences of SEQ ID NOs: 234 and 235, which comprises the CDR-H1-3 having the sequences of SEQ ID NOs: 147, 153 and 156 paired to CDR-L1-3 having the sequences of SEQ ID NOs: 159, 172, and 195, but not the antibodies with Mixed and Matched VH and VL or antibody fragment containing only one VH or VL domain as recited in claims, 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).
Response to applicant’s argument:
Starting at page 9, applicant argues:
Applicant submits that amended independent claims 42 and 52 require a full set of 6 CDRs, thus obviating part 2) of the rejection.
……. the claims as amended related to polynucleotides and host cells comprising polynucleotides encoding VH/VLs from a group of highly structurally and functionally similar antibodies, all derived from the parental antibody designated 14D 10.
A person of ordinary skill in the art at the time of filing would reasonably have expected that any combination of the disclosed VH and VL domains from these related antibodies would result in an antibody that retained the desired binding.
In response, the Office agrees on that the amended claims 42 and 52 have overcome the rejection of the antibody containing only one domain, VH or VL. However, the claims as written still encompass Mixed and Matched VH and VL even the antibody variants are from the same parental antibody because the sequences of CDRs in both VHs and VLs are totally alternated, which would result in changing the characteristics the original antibody including antigen recognition and affinity of antigen binding. Thus, without reduced practice of antigen binding test with a paired VH and VL, one skilled in the art would not consider that randomly paired VH and VL of the claimed antibody variants with random amino acid alternations in CDRs have the same activities as the parental antibody, binding to the same MuSK protein. To overcome the rejection, applicant should consider to amend the claims reciting an antibody having VH and VL pairs as newly added claims 64 and 65.
Improper Markush Grouping
Claims 42-46 and 52-56 remain and newly added claims 62-63 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 706.03(y).
The Markush groupings of VHs and VLs (e.g. claim 42) and CDR-H1-3 and CDR-L1-3 (e.g. claim 43) are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
each of the antibodies has unique CDRs and VH/VL sequences which are not shared by the other antibody listed in the claims. The elected antibody comprising VH of SEQ ID NO: 234 comprising CDR-VH1-3 of SEQ ID Nos: 147, 153, and 156 and VL of SEQ ID NO: 235 comprising CDR-VL1-3 of SEQ ID Nos: 159, 172, and 195 does not share and have common structure in sequences and binding function with the other antibody in the list.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Response to applicant’s argument:
At page 10, applicant provides the same argument as above, specifically,
the present claims relate to polynucleotides and host cells comprising polynucleotides encoding VH/VLs from a group of highly structurally and functionally similar antibodies, all derived from the parental antibody designated 14D10. Each of the tested clones showed high affinity for human MuSK (Figure 19 and 22, Tables 4 and 8) and induced MuSK phosphorylation in C2C12 myotube mouse muscle fibers (Table 6 and Figure 21).
In response, as discussed above all antibodies claimed in the field have similar structures including CDRs in VH and VL regions and Fc as constant region. However, applicant and one skilled in the art would also agree those antibodies cross the biological field binding to totally different and unrelated antigens and performing different biological functions. Thus, as stated in the rejection above each of the antibodies with variant CDRs would not consider as having the same structures and could not perform the same functions. As we discussed in the interview with applicant’s representative, the Office would consider to rejoin the antibodies with the same VH domain to pair different but similar VL domains to move the application forward, unfortunately, there is not agreement made at this time (see interview summary).
NEW GROUND REJECTION-based on the claim amendment
Claim Rejections - 35 USC § 112
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 44 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.
In order to be a proper dependent claim, the dependent claim should include all the limitations of its base claim and further limit the base claim. Base claim 42 recites:
An isolated polynucleotide encoding a heavy chain variable region (VH) and a light chain variable region (VL) of an antibody that specifically binds to human muscle-specific tyrosine-protein kinase (MuSK), wherein
(a) the VH comprises a CDR-H1, a CDR-H2, and a CDR-H3 of the VH amino acid sequence of SEQ ID NO: 196,198,…….. 234, 236,…and
(b) the VL comprises a CDR-L1, a CDR-L2, and a CDR-L3 of the VL amino acid sequence of SEQ ID NO: 197, 199,,………..235, 237,…..
the dependent claim 44 further limits the antibody encoded by polynucleotide and recites:
(a) the VH comprises an amino acid sequence that is at least 80% identity to the amino acid sequence of SEQ ID NO: 196,198…….. 234, 236 and/or
(b) the VL comprises an amino acid sequence that is at least 80% identity to the amino acid sequence of SEQ ID NO: SEQ ID NO: 197, 199,,………..235, 237,…..
Since the antibody in base claim 42 has already contained both VH and VL domains, the antibody of claim 44 containing VH or VL domain is broader, which does not further limit the previous claim 42.
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.
Claim Objection
Claims 64-65 are objected to as being dependent upon a rejected base claim 42, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Claims 42-63 are rejection, claims 64-65 are objected, and No claim is 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 extension fee 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 Lei Yao, whose telephone number is (571) 272-3112. The examiner can normally be reached on 8:00am-6:00pm Monday-Friday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached on (571) 270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LEI YAO/ Primary Examiner, Art Unit 1642