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 .
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 5-8, 10, 13, 22, and 30 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more.
Claims 5-8, 10, 22, and 13 recite an anti-o-mannosylated E-cadherin antibody. Claims 5, 6, 7, 8, 10, 11, and 13 encompass the naturally occurring antibody obtained from a human patient blood sample; see Example 1. The naturally occurring antibody is taught as having the CDRs of SEQ ID NOs: 69-71, 62, the residues WAS, and SEQ ID NO: 63 and the heavy and light variable regions of SEQ ID NOs: 1 and 18; pages 39-40 and Table 1 referencing antibody AT1636. The sequences recited in claims 5, 6a, 7, and 8 encompass those of the naturally occurring antibody and are not markedly distinct. Claim 10 recites naturally occurring antibody isotypes, including IgG which is the isotype of the naturally occurring antibody. Claim 13 merely recites inherent binding characteristics of the anti-o-mannosylated E-cadherin antibody AT1636 which do not amount to a markedly distinct product. While the claims have been amended to recite a synthetic or recombinant antibody or antibody fragment, the limitations synthetic or recombinant are not defined in the Specification and do not confer a structural distinction from the antibody which is naturally occurring.
Claim 22 recites a codon optimized nucleic acid sequence. The naturally occurring nucleic acid sequence encoding the human antibody of claim 5 is codon-optimized for a human. Thus, the claim is not limited to something markedly different from the naturally occurring antibody. Claim 22 may be withdrawn from this rejection if any one of the following amendments are made: 1. Removing the naturally occurring sequences or sequences which encompass those naturally occurring sequences in claim 5 (see the previous page), 2. Limiting the producer cell to be non-human (see the definition of codon optimized on page 72), or 3. Restricting the singular nucleic acid to comprise sequences encoding both the heavy and light chain variable regions or encoding all six CDRs (these sequences are found on different chromosomes naturally).
Claim 30 recites a composition comprising the antibody of claim 5. There is no limiting definition for composition in the Specification. A composition is interpreted as comprising the antibody and a diluent or carrier as supported in the embodiments taught on page 100 lines 4-10. This diluent or carrier encompasses sera. Thus, the claim reads on the naturally occurring antibody in blood.
This judicial exception is not integrated into a practical application because these claims simply recite the products encompassing those which are naturally occurring without requiring further limitations which distinguish the products claimed from those taught in the Specification to occur naturally. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because no additional elements are claimed which distinguish the products claimed from those taught in the Specification to occur naturally.
Thus, claims 5-8, 10, 13, 22, and 30 are rejected under U.S.C. 101 as being drawn to products of nature.
Claim Rejections - 35 USC § 112(a)
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 5, 7, 8, 11, 13, 14, 17-20, 22, 25, 26, 28, 30, 33, 34, 41-43, and 48-51 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.
Claims 5, 7, 8, 20, 48, and 49 recite partial structures of the anti-o-mannosylated E-cadherin antibodies or antigen binding fragments. Claim 5 recites that any CDR may have up to 3 conservative substitutions. In its broadest embodiment, the anti-o-mannosylated E-cadherin antibody may comprise a light chain CDR2 comprising the residues WAX where X is S or C, which comprises up to 3 conservative mutations thereby entirely changing the sequence of the light chain CDR2 in its entirety. Additionally, claim 48 recites a partial requiring only a single CDR of a common light chain. Common light chain is defined on page 35 line 35 to page 36 line 2 as a light chain that is able to functionally pair with a plurality of different heavy chains, whereby the antigen specificity of said heavy chains is maintained.
Claim 7 recites partial structures having at least 90% identity to the VH and/or VL sequences recited. Claim 8 recites partial structures having 90% sequence identity to the VH and VL sequences recited. Because claim 5, from which both claims 7 and 8 depend, recite a set of six CDRs each with up to 3 conservative substitutions, the variability in VH and/or VL sequences encompass variations of the CDRs. If claim 5 were amended to remove the limitation allowing up to 3 conservative substitutions such that all six CDRs are required and defined, the variability of at least 90% identity in claims 7 and 8 would be acceptable as by dependency claims 7 and 8 would be constrained to having the CDRs of SEQ ID NOs: 59, 60, 61, 62, and 63 and the residues WAX.
Claim 20 recites a CAR T cell that comprises the heavy chain CDR1, CDR2, and CDR3 of claim 5, but does not require any light chain CDRs. Additionally, claim 49 recites formats that comprise only a heavy chain or the three heavy chain CDRs - “a single domain antibody or nanobody” and “an Fd fragment”.
It is well-known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope. 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, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proc. Nat.l Acad. Sci. U.S.A. 79(6): 1979-1983; Published: March 1982). Rudikoff et al. teaches that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. Similarly, MacCallum et al. (Journal of Molecular Biology. 262: 732-745; Published: 1996) analyzed many different antibodies for interactions with antigen and states that although CDR3 of the heavy and light chain dominate, a number of residues outside the standard CDR definitions make antigen contacts and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations; see page 733 right column and 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. 307: 198-205; Published: 2003), 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. 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 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 199 left column and page 202 left column. Vajdos et al. (Journal of Molecular Biology. 320: 415-428; Published: 2002), additionally states 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. 294: 151-162; Published: 1999) states 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, but certain residues have been identified as important for maintaining conformation; see page 152 left column. Padlan et al. (PNAS. 86: 5938-5942; Published: 1989) describes the crystal structure of an antibody-lysozyme complex where all 6 CDRs contribute at least one residue to binding and one residue in the framework is also in contact with antigen.
Lastly, regarding the significance of light chain CDRs, Lamminmaki et al. (JBC. 276: 36687-36694; Published: 2001) describes the crystal structure of an anti-estradiol antibody in complex with estradiol where, although CDR3 of VH plays a prominent roll, all CDRs in the light chain make direct contact with antigen (even CDR2 of VL, which is rarely directly involved in hapten binding). Similarly, Murphy et al. (Journal of Immunological Methods. 463: 127-133; Published: October 12, 2018), teach that altering amino acid D92 in the complementarity determining region light chain region 3 (CDRL3) of single chain fragment variable (scFv) 2G1 obliterates its capacity to bind to microcystinleucine-arginine (MC-LR) and changing phenylalanine at position 91 to tyrosine caused an increased in binding to MC-LR, compared to the parent clone; see page 130, Section 3.2, paragraph 2 and page 131, column 1, paragraph 2. The alterations in binding that were observed in these two variants demonstrate the highly influential role of CDRL3 in binding MC-LR.
The Specification does not teach any antibody which does not comprise all 6 of the CDRs disclosed in claim 6 and is capable of binding o-mannosylated E-cadherin. Similarly, the Specification does not demonstrate any single domain antibody or Fd fragment formats, which comprises only 3 heavy chain CDRs of claim 6 and is capable of binding o-mannosylated E-cadherin. Additionally, regarding the common light chain of claim 48, Applicant discloses only 5 light chains which differ from each other by 1 or 2 residues. There is no further guidance regarding the structure which makes a light chain function as a common light chain. Regarding the phrase “1, 2, or 3 conservative substitutions” to each of the CDRs, the instant disclosure, while exemplifying what is considered a conservative substitution in Table 2, does not provide any guidance regarding which residues, if any, within each of the CDRs may be substituted while maintaining the ability to bind o-mannosylated E-cadherin.
Given the breath of the claims, the unpredictability in the art, and the lack of guidance in the Specification, one of ordinary skill in the art would not conclude that Applicant was in possession of the antibodies claimed by partial structures.
Additionally, claims 10, 11, 13, 14, 17-20, 22, 25, 26, 28, 30, 33, 34, 41-43, and 48-51 depend from claim 5 and do not remedy the failure to comply with the written description requirement.
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 17 and 49 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.
Regarding claim 17, it is unclear what the word “coupled” in line 2 signifies. Does the claim mean to recite compounds conjugated or covalently bound to the antibody? Are other interactions (e.g. ionic) encompassed in the word coupled? Because the word coupled is used when defining antibody-drug conjugates which are typically antibodies covalently linked to a drug on page 83 lines 30-34 of the Specification, the limitation “coupled” is interpreted to mean covalently linked, for the purpose of compact prosecution.
Claim 49 contains the trademark/trade name nanobody. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe an antibody format and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 112(d)
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 51 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 51, which depends from claim 17 and claim 17 depends from claim 14, recites that the antibody is bispecific or multispecific. Claim 17 recites that “antibody or antibody binding fragment is coupled” to a CD3 or TGFβ binding compound. The “antibody or antibody binding fragment” in line 2 of claim 17 is interpreted to refer back to the overall structure of claim 14 and not the “second antibody or antigen binding part” in lines 7 and 8 of claim 14 which has a slightly different name. In claim 14, the anti-E-cadherin antibody may be covalently linked to a second antibody, then in claim 17 that bispecific antibody is then “coupled” to a CD3 or TGFβ binding compound, which would result in something trispecific or multispecific. Also, the anti-E-cadherin antibody may be covalently linked to a second antibody, which is bispecific, then in claim 17 that trispecific antibody is then “coupled” to a CD3 or TGFβ binding compound, which would result in something multispecific. And, finally, the anti-E-cadherin antibody may be covalently linked to a cytokine, then in claim 17 that antibody-cytokine conjugate is then “coupled” to a CD3 or TGFβ binding compound, which would result in something bispecific. Thus, the recitation in claim 51 that the antibody is bispecific or multispecific does not specify a further limitation.
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.
Improper Markush Grouping
Claim 14 is 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 § 2117.
The Markush grouping of claim 14 is 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: The claim recites compounds which encompass small molecule inhibitors (e.g. a drug, a drug, a cytotoxic agent), recombinant or fusion proteins (e.g. a cytokine, a hormone, an enzyme), antibodies (e.g. a second antibody or antigen binding part thereof, a cell-binding agent), a detectable label, and nucleic acid molecules. The compounds recited in the alternative in claim 14, being made of distinct structural elements (chemicals, nucleic acids, or proteins) lack a single structural similarity. Additionally, since some are used for detection or diagnostics (i.e. a detectable label) and some are used cancer treatment (i.e. a chemotherapeutic agent), the alternatives do not share a common use.
Thus, claim 14 does not recite alternative compounds which are functionally equivalent and have a common use.
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 Arguments
Applicant’s amendments filed October 30, 2025 are acknowledged. Any rejection not repeated above is resolved by amendment.
Regarding the rejection of claims 5, 7, 8, 11, 13, 14, 17-20, 22, 25, 26, 28, 30, 33, 34, 41-43, and 48-51 as failing to satisfy the written description requirement, the claims still recite antibodies comprising CDRs which may comprise up to three conservative substitutions. The criticality of CDR sequences to antigen specificity and the impact of even a single substitution are described above. Additionally, it was noted that the light chain CDR2 is only three residues long and three conservative substitutions would yield a distinct CDR. Despite claiming such a broad genus of antibodies, the instant disclosure only demonstrates the binding specificity of antibodies comprising the six CDR of SEQ ID NOs: 59, 60, 61, 62, and the residues WAX, where X is S or C, and without any conservative substitutions. Applicant argues that “[g]iven that the key structural requirements that determine the binding specificity of the claimed antibody or antigen binding fragment are recited in the present claims, the claims are believed to satisfy the written description requirement.” Indeed, the claims recite a set of six defined CDRs, but with option for each CDR to comprise up to three conservative substitutions. The potential number of permutations of CDRs with up to three conservative substitutions per CDR is enormous. In contrast, Applicant only demonstrates the binding specificity of variants recited in claim 6 – variants which do not comprise any conservative substitutions. The extent to which the instant disclosure teaches to these conservative to substitutions is the inclusion of a table of “non-limiting examples of conservative amino acid substitutions”. There is no further guidance regarding substitutions. Additionally, claims 20, 48, and 49 encompass antibodies which comprise fewer than all six of the CDRs. The instant Specification does not teach any anti-E-cadherin antibodies which comprise fewer than six CDRs. One would not conclude based on the instant disclosure that Applicants were in possession of the full scope of claims 5, 20, 48, and 49.
Regarding the rejection under 35 U.S.C. 101, the limitation “synthetic or recombinant” are not defined in the Specification. While these terms describe a means of production, they do not confer a structural distinction from that anti-E-cadherin antibody which is naturally occurring. The rejection under 35 U.S.C. 101 over claims 5, 6, 7, 8, 10, 13, 22, and 30 is maintained. Vectors are not naturally occurring. Thus, the rejection of claim 28 under 35 U.S.C. 101 is withdrawn. Finally, regarding claim 11, while afucosylation occurs in naturally produced antibodies, there is no evidence in the Specification that the naturally occurring antibody AT1636 is afucosylated, hypergalactosylated or comprising a modified Fc region. Thus, the rejection of claim 11 under 35 U.S.C. 101 is withdrawn. Finally, the rejection of claim 22 is maintained. Codon optimized, even as defined on instant page 72 is a relative term, codon optimized for production in a non-human cell could overcome the rejection.
Allowable Subject Matter
While no claim is currently allowable, an anti-o-mannosylated E-cadherin antibody comprising SEQ ID NOs: 59-62, WAX wherein X is S or C, and SEQ ID NO: 63 is not taught by the prior art. Similarly, anti-o-mannosylated E-cadherin antibodies comprising the sequences recited in claim 6 or comprising the heavy and light chain variable regions comprising SEQ ID NOs: 1-17 and 18-22 are not taught in the prior art.
The closest prior art is of Lommel et al. (PNAS. 110(52): 21024-21029; Published: December 24, 2013) which teaches generating an antibody against the peptide, CYAT(1α-Man)AV, in order to identify o-mannosylated cadherins. The reference does not teach the sequence of the antibody nor that it binds to positions 467-472 of E-cadherin (instant SEQ ID NO: 45). Nor does the sequence of the peptide used to generate the antibody align with 100% identity mannosylated site instantly claimed, which comprises the amino acid sequence TTSTAT.
Conclusion
THIS ACTION IS MADE FINAL. 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 KATHERINE ANN HOLTZMAN whose telephone number is (571)270-0252. The examiner can normally be reached Monday - Friday 8:30am - 5:00pm MT.
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/KATHERINE ANN HOLTZMAN/
Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682