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 .
Application Status
Claims 83-102 are pending and examined on the merits herein.
Claim Objections
Claim 102 is objected to because of the following informalities:
Line 1 recites “A polynucleotide comprising a polynucleotide encoding” it should read “A polynucleotide encoding”;
Options (c) and (d) of claim 102 are substantial duplicates of options (a) and (b) just stated in the reverse.
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 99 and 103 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 99 is written to depend from claim 1 which is a cancelled claim. This renders claim 99 indefinite as the metes and bounds of the claim are unclear.
Claim 101 depends from claim 99 and is therefore included in this rejection.
For the purpose of compact prosecution claim 99 will be examined as dependent from claim 83.
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 83-84 and 98-101 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.
Regarding instant claim 83, the disclosure does not test mixing and exchange of the antibody CDR regions of separate antibody CDRH1-H3 and CDRL1-L3 outside of CDRs present in the I2676, I2677, I3144, I3145, I3210 and I3213 clones that possess the recited function of binding CCR8. Instant claim 84 further allows heavy and light chain exchange. Instant claims 98-101 are dependent on instant claim 83 without narrowing the CDRs to those tested and present in the I2676, I2677, I3144, I3145, I3210 and I3213 clones.
Scope of the claimed genus
Claim 83 claims an antibody or antigen-binding fragment thereof that binds CD19 comprising sequences for CDRH1-H3 and CDRL1-L3, wherein the CDRs that were present in the I2676, I2677, I3144, I3145, I3210 and I3213 clones can be exchanged to produce separate antibodies wherein,
CDRH1 comprises the amino acid sequence of SEQ ID NO: 9, 15, 21, or 27;
CDRH2 comprises the amino acid sequence of SEQ ID NO: 10, 16, or 28;
CDRH3 comprises the amino acid sequence of SEQ ID NO: 11, 17, 23, or 29;
CDRL1 comprises the amino acid sequence of SEQ ID NO: 12, 30, or 42,
CDRL2 comprises the amino acid sequence of SEQ ID NO: 13, 31, or 37;
CDRL3 comprises the amino acid sequence of SEQ ID NO: 14, 20, or 32.
State of the Relevant Art
At the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
In addition to changes within the CDR altering target binding, alterations to the CDR have been shown to dramatically alter antibody secretion. Hasegawa H et al. (mAbs 2017, 9(5) 854-873) taught a pair of human IgG clones with a single amino acid substitution in the variable region was sufficient to alter the efficiency of immunoglobulin biosynthesis (page 866, last sentence left column). Hasegawa taught the 2 mAbs differed only by one amino acid in the LC's CDR1 and that despite the near-identity of their primary sequences, the parental mAb secreted copious amounts of IgG to the culture media, while the variant mAb induced RB phenotypes extensively and secreted 20-fold less IgG (page 866, right column, first paragraph). Importantly, the 2 model IgGs were by no means abnormal or defective as mAbs, but demonstrated a profound impact of a single amino acid substitution on immunoglobulin biosynthesis (page 866, right column, first paragraph).
Summary of Species disclosed in the original specification
MPEP § 2163 states that 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 specification identifies that antibodies in tables 1 and 2 (pages 39-41) with clone names I2676, I2677, I3144, I3145, I3210 and I3213 with the ability to bind to CCR8 (Fig 8-11). The specification further teaches in some embodiments a humanized anti-CCR8 antibody is provided that competes for binding to CCR8 with an antibody selected from I2676, I2677, I3144, I3145, I3210 and I3213 (page 44, lines 20-22).
Alignment of the CDR regions of the CCR8 antibodies of the I2676, I2677, I3144, I3145, I3210 and I3213 clones show the antibody CDRs have several regions that are distinct and have no overlap. Multiple changes within the CDR region would cause unpredictable binding effects on the claimed antibody target CD19 and antibody secretion.
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The specification does not have examples of exchange of CDR-H1-H3 and CDRL1-L3 with the SEQ ID NOs identified in instant claim 83 to form antibody or antigen-binding fragments that bind to CCR8 outside of an antibody or antigen-binding fragment thereof that binds CCR8 comprising:
i) CDRH1-H3 of SEQ ID NO: 9-11 and CDRL1-L3 of SEQ ID NO: 12-14;
ii) CDRH1-H3 of SEQ ID NO: 15-17 and CDRL1-L3 of SEQ ID NO: 12, 13 and 20;
iii) CDRH1-H3 of SEQ ID NO: 21, 16, and 23 and CDRL1-L3 of SEQ ID NO: 12, 13, and 20;
iv) CDRH1-H3 of SEQ ID NO: 27-29 and CDRL1-L3 of SEQ ID NO: 30-32;
v) CDRH1-H3 of SEQ ID NO: 9-11 and CDRL1-L3 of SEQ ID NO: 12, 37, and 14; and
vi) CDRH1-H3 of SEQ ID NO: 9-11 and CDRL1-L3 of SEQ ID NO: 42, 13, and 14.
As noted above, the art generally accepted that the combination of the CDRs within the VH and VL pair of an antibody were essential for binding specificity. But the specification does not describe what residues within the CDRs confer the binding activity claimed and the claim language permits changes in the VH and VL that contain the CDRs or exchanging of the VH or VL. Accordingly, the skilled artisan would not be able to discern a structure/function correlation for multivalent peptides other than those comprising all six CDRs or both the VH and VL of the antibody or antigen fragment of the CCR8 antibody clones present together in I2676, I2677, I3144, I3145, I3210 and I3213.
The description of six species of separate CCR8 antibodies with little overlap, and the fact that the species that were described cannot be considered representative of the broad genus, Applicant was not in possession of the invention as claimed.
Summary
A genus of species is not present in the instant specification or prior art that would demonstrate a structure activity relationship would be known for antibody CDR residues for the recited function of binding the protein target CCR8. There is a lack of an appropriate number of species with identical or alternative amino acid residues within the CDR binding determinant region that indicate which amino acid residues: i) are essential for binding; ii) can be changed and still allow protein target binding; and iii) disrupt protein target binding. One of skill in the art would reasonably conclude that applicant was not in possession of the required genus of CDR exchanges or VH/ VL exchanges for a CCR8 antibody at the time of filing.
Allowable Subject Matter
Claims 85-97 are 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.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMBER K FAUST whose telephone number is (703)756-1661. The examiner can normally be reached Monday - Thursday 9:00am-6:00pm EST.
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/AMBER K FAUST/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643