DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 20-30, 34-37, 42, 43, 47, 64 and 72 are pending.
Election/Restrictions
Applicant’s election without traverse of Group 2 in the reply filed on March 2, 2026 is acknowledged. Applicant’s election without traverse of the antibody clone B3-1 in the reply filed on March 2, 2026 is acknowledged. Claims 20, 35-37, 43, 47, 64 and 72 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim.
Claims 21-30, 34 and 42 are under examination.
Drawings
The drawings are objected to because the caption for FIGS. 7L-M on page 17 of the drawings should read FIGS. 7L-N. In addition, the caption for FIGS. S4A-G. is missing from page 25. The caption on page 27 for FIG. SE should recite FIG. 5SE. The caption for FIGS. S6A-H, FIG. S8, FIGS. S11A1 and FIG. S12 on pages 28, 31 34, 35 and 37 respectively, are missing. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 21-30, 34 and 42 are objected to because of the following informalities: The claim refers to “Tables 3 and 4” however, the claims should recite the relevant material from Tables 3 and 4 in the claims for clarity. MPEP states: “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993). Reference characters corresponding to elements recited in the detailed description and the drawings may be used in conjunction with the recitation of the same element or group of elements in the claims. See MPEP § 608.01(m).” Appropriate correction is required.
Claim Rejections – Improper Markush Grouping
Claims 21-30, 34 and 42 are rejected on the judicially-created basis that they contain 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 claims 21-30, 34 and 42 are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use that flows from the substantial structural feature for the following reasons:
Claim 21 is drawn to an isolated monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain (HC) variable region (VH) and a light chain (LC) variable region (VL) comprising clone-paired CDR sequences as set forth in Tables 3 and 4; and variants thereof wherein one or more of the HC-CDRs and/or LC-CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof The antibodies of claim 21-30, 34 and 42 do not share both a single structural similarity or feature (CDRs or FRs) and a common use that flows from the structural feature as shown in Table [00112], page 19. For example, a comparison of some of the Heavy chain CDRs amino acid sequences and their corresponding SEQ ID NOs of Table 3 is listed in the table:
VH CDR 1
VH-CDR-2
VH-CDR-3
SEQ ID NO:
256
169
257
GFTFSSYG
IRYDGSNK
AKAGFSGWYYYGMDV
SEQ ID NO:
171
172
47
GDSVSSNSAA
TYYRSKWYN
ARALAGIDGFDV
SEQ ID NO:
174
175
49
GYTFTSYY
INPSGGST
ARGETGRFGELIRGMDV
The antibodies of claim 21 have distinct CDR set amino acid sequences thus will likely bind different epitopes. The claims recite discrete antibody binding domains and do not all share significant structural similarity since it is the entire CDR set that is required to bind antigen. This is evidenced by the fact that 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 (Proc Natl Acad Sci USA 1982 Vol 79 page 1979). Rudikoff teaches that the alteration of a single amino acid in a single CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (entire article, Abstract).
Although only a few VH CDRs are used as an example, an artisan would understand that the sequence differences in the CDRs overall would amount to structural differences in the antibody binding region as a whole, and therefore there would be no structural similarity between the antibodies leading to be functionally equivalent and to their common use.
Dependent claims are rejected for failing to resolve the improper Markush grouping. 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.
This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. §134 and 37 CFR 41.31(a)(1) (emphasis provided).
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.
Claims 21-30, 34 and 42 are rejected under 35 U.S.C. 112(a), 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.
The claims are drawn to an isolated monoclonal antibody comprising a heavy chain (HC) variable region (VH) and a light chain (LC) variable region (VL) comprising a variable heavy chain complementarity determining region 1 (VH CDR1) of SEQ ID NO: 168; a VH CDR2 of SEQ ID NO: 169; a VH CDR3 of SEQ ID NO: 170; a variable light chain complementarity determining region 1 (VL CDR1) of SEQ ID NO: 256; a VL CDR2 of GAS and a VL CDR3 of SEQ ID NO: 257, wherein one or more of the HC-CDRs and/or LC-CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof.
The specification discloses an isolated monoclonal antibody comprising a heavy chain (HC) variable region (VH) and a light chain (LC) variable region (VL) comprising a variable heavy chain complementarity determining region 1 (VH CDR1) of SEQ ID NO: 168; a VH CDR2 of SEQ ID NO: 169; a VH CDR3 of SEQ ID NO: 170; a variable light chain complementarity determining region 1 (VL CDR1) of SEQ ID NO: 256; a VL CDR2 of GAS and a VL CDR3 of SEQ ID NO: 257.
The specification does not disclose any examples disclosing which amino acids of the antibody may be substituted, added or deleted and maintain binding to LILRB3.
The state of the prior art is such that it is well established in the art that the formation of an intact antigen-binding site of antibodies routinely 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 the 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 (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30). 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. Natl. Acad. Sci. USA, 79(6):1979-1983, March 1982). Rudikoff et al. teach 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. Colman P. M. (Research in Immunology, 145:33-36, 1994) teaches that even a very conservative substitution may abolish binding or may have very little effect on the binding affinity (see pg. 35, top of left column and pg. 33, right column). While there are some publications, which acknowledge that CDR3 is important, the conformations of other CDRs as well as framework residues influence binding. MacCallum et al (J. Mol. Biol., 262, 732-745, 1996) 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 (Biochemical and Biophysical Research Communications, 2003, Vol. 307, pp. 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.) 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 col.). Holm et al (Molecular Immunology, 2007, Vol. 44, pp. 1075-1084) describes the mapping of an anti-cytokeratin antibody where although residues in the CDR3 of the heavy chain were involved in antigen binding unexpectedly a residue in CDR2 of the light chain was also involved (abstract).
It is unlikely that antibodies, which do not contain all of the specific heavy and light chain CDRs of B3-1 in their proper order and in the context of framework sequences, which maintain their correct spatial orientation, have the requisite LILRB3 binding function. The specification provides insufficient evidence or nexus that would lead the skilled artisan to predict the ability of making substitution, additions and deletions to the claimed CDRs and maintained binding to LILRB3. The specification does not disclose any examples disclosing which amino acids of the antibody may be substitutions, additions, deletions, or combinations thereof and maintain binding to LILRB3, wherein the antibodies bind LILRB3.
The specification does not provide adequate written description of the claimed genus of antibodies comprising a heavy chain (HC) variable region (VH) and a light chain (LC) variable region (VL) comprising a variable heavy chain complementarity determining region 1 (VH CDR1) of SEQ ID NO: 168; a VH CDR2 of SEQ ID NO: 169; a VH CDR3 of SEQ ID NO: 170; a variable light chain complementarity determining region 1 (VL CDR1) of SEQ ID NO: 256; a VL CDR2 of GAS and a VL CDR3 of SEQ ID NO: 257, wherein one or more of the HC-CDRs and/or LC-CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof. The legal standard for sufficiency of a patent's (or a specification's) written description is whether that description "reasonably conveys to the artisan that the inventor had possession at that time of the. . .claimed subject matter", Vas-Cath, Inc. V. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991). In the instant case, the specification does not convey to the artisan that the Applicant had possession at the time of invention the genus of antibodies that bind LILRB3.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicant was in possession of the genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, Fri. January 5, 2001, see especially page 1106 column 3).
The specification does not provide adequate written description of the claimed invention. The legal standard for sufficiency of a patent's (or a specification's) written description is whether that description "reasonably conveys to the artisan that the inventor had possession at that time of the. . .claimed subject matter", Vas-Cath, Inc. V. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991). In the instant case, the specification does not convey to the artisan that the Applicant had possession at the time of invention of the claimed invention, the genus of isolated monoclonal antibodies comprising a heavy chain (HC) variable region (VH) and a light chain (LC) variable region (VL) comprising a variable heavy chain complementarity determining region 1 (VH CDR1) of SEQ ID NO: 168; a VH CDR2 of SEQ ID NO: 169; a VH CDR3 of SEQ ID NO: 170; a variable light chain complementarity determining region 1 (VL CDR1) of SEQ ID NO: 256; a VL CDR2 of GAS and a VL CDR3 of SEQ ID NO: 257, wherein one or more of the HC-CDRs and/or LC-CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof. The specification does not disclose any examples disclosing which amino acids of the antibody may be substituted, added or deleted and maintain binding to LILRB3.
The Federal Circuit addressed the application of the written description requirement to DNA-related inventions in University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997). The court stated that “[a] written description of an invention involving a chemical genus, like a description of a chemical species, requires a precise definition, such as by structure, formula, [or] chemical name, of the claimed subject matter sufficient to distinguish it from other materials.” Id. At 1567, 43 USPQ2d at 1405. The court concluded that “naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.” Id.
The Federal Circuit clarified that a molecule can be adequately described without disclosing its complete structure. See Enzo Biochem, Inc. V. Gen-Probe Inc., 296 F.3d 1316, 63 USPQ2d 1609 (Fed. Cir. 2002). The Enzo court adopted the standard that the written description requirement can be met by “show[ing] that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics ....i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. “ Id. At 1324, 63 USPQ2d at 1613 (emphasis omitted, bracketed material in original).
However, without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
Thus, the instant specification may provide an adequate written description of the genus of antibodies comprising a heavy chain (HC) variable region (VH) and a light chain (LC) variable region (VL) comprising a variable heavy chain complementarity determining region 1 (VH CDR1) of SEQ ID NO: 168; a VH CDR2 of SEQ ID NO: 169; a VH CDR3 of SEQ ID NO: 170; a variable light chain complementarity determining region 1 (VL CDR1) of SEQ ID NO: 256; a VL CDR2 of GAS and a VL CDR3 of SEQ ID NO: 257, wherein one or more of the HC-CDRs and/or LC-CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof, per Lilly by structurally describing a representative number of anti-LILBR3 antibodies or by describing structural features common to the members of the genus, which features constitute a substantial portion of the genus.
It is noted that AbbVie v. Janssen Biotech and Centocor Biologics (Fed. Cir. 2014) confirms a strong Post-Ariad Written Description requirement - especially with regard to genus-species claim situations. In the decision, Judge Lourie focuses particularly on the alleged infringing antibodies and notes that: [While] AbbVie patents need not describe the allegedly infringing [compound] in exact terms . . . [t]he patents must at least describe some species representative of antibodies that are structurally similar to [the accused compound]. Because the patent document lacked any such structural description, the court confirmed that the corresponding claims were invalid under 112(a). In discussing the case, Judge Lourie was clear that one problem here is that the invention was described in terms of its function rather than its structure. Lourie writes:
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The Court has indicated in Amgen Inc vs Sanofi ( 2017-1480, Fed Cir, 2017) that the disclosure of a well characterized antigen is insufficient for an adequate written description of the antibody that binds the antigen. The Court stated that “an adequate written description must contain enough information about the actual makeup of the claim products – a precise definition such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other material,” which may be present in “function “terminology “when the art has established a correlation between structure and function” (page 17, 1st paragraph). The Court went on to indicate that knowledge of the chemical structure of an antigen does not tell you anything about the structure of the antibody (Id).
In this case, the specification does not appear to describe the genus of antibodies comprising a heavy chain (HC) variable region (VH) and a light chain (LC) variable region (VL) comprising a variable heavy chain complementarity determining region 1 (VH CDR1) of SEQ ID NO: 168; a VH CDR2 of SEQ ID NO: 169; a VH CDR3 of SEQ ID NO: 170; a variable light chain complementarity determining region 1 (VL CDR1) of SEQ ID NO: 256; a VL CDR2 of GAS and a VL CDR3 of SEQ ID NO: 257, wherein one or more of the HC-CDRs and/or LC-CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof and thus does not satisfy either the Lilly nor Enzo standards. The specification does not disclose any examples disclosing which amino acids of the antibody may be substituted, added or deleted and maintain binding to LILRB3.
There are insufficient structural features common to all members of the genus of anti-LILRB3 antibodies. However, the specification does not disclose sufficient information on the structural function relationship to identify the claimed genus of anti-LILRB3 antibodies. One of ordinary skill in the art would not be able to identify the broad claimed genus of antibodies comprising a heavy chain (HC) variable region (VH) and a light chain (LC) variable region (VL) comprising a variable heavy chain complementarity determining region 1 (VH CDR1) of SEQ ID NO: 168; a VH CDR2 of SEQ ID NO: 169; a VH CDR3 of SEQ ID NO: 170; a variable light chain complementarity determining region 1 (VL CDR1) of SEQ ID NO: 256; a VL CDR2 of GAS and a VL CDR3 of SEQ ID NO: 257, wherein one or more of the HC-CDRs and/or LC-CDRs has one, two, or three amino acid substitutions, additions, deletions, or combinations thereof.
Thus, the specification does not provide an adequate written description of the genus of anti-LILRB3 antibodies that is required to practice the claimed invention. Applicants have not described the genus of anti-LILRB3 antibodies sufficiently to show they had possession of the claimed genus. Since the disclosure fails to provide sufficient relevant identifying characteristics, and because the genus is highly variant, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus as broadly claimed.
Summary
No claims allowed.
There is no prior art on an isolated monoclonal antibody comprising a heavy chain (HC) variable region (VH) and a light chain (LC) variable region (VL) comprising a variable heavy chain complementarity determining region 1 (VH CDR1) of SEQ ID NO: 168; a VH CDR2 of SEQ ID NO: 169; a VH CDR3 of SEQ ID NO: 170; a variable light chain complementarity determining region 1 (VL CDR1) of SEQ ID NO: 256; a VL CDR2 of GAS and a VL CDR3 of SEQ ID NO: 257
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/MARK HALVORSON/ Primary Examiner, Art Unit 1646
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