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 .
Claims 1-11, 14-15 and 17-21 are pending.
Applicant’s election without traverse of Group I that read on (A) CD32b as the particular inhibitor receptor, (B) CD38 as the particular targeting marker, (C) SEQ ID NO: 11, CD12 (CD38) and SEQ NO: 21 and 22 (CD38), (D) antibody that binds to CD32b and CD38, in the reply filed on September 5, 2025 is acknowledged.
Claims 14 and 18-21 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 1-11, 15 and 17, drawn to a multi-specific antibody comprising at least two different antigen binding regions (ABR) that bins to an extracellular domain of a particular inhibitory receptor expressed on activated immune cells and a second ABR that specifically binds to a target marker that read on (A) CD32b as the particular inhibitor receptor, (B) CD38 as the particular targeting marker, (C) SEQ ID NO: 11, CD12 (CD38) and SEQ NO: 21 and 22 (CD38), (D) antibody that binds to CD32b and CD38, are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 63/008,423, filed April 10, 2020, is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on July 9, 024 and Oct 6, 2022 have been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
The listing of references in the specification at pages 44-45 is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings filed on Oct 6, 2022 are acceptable.
Specification
The substitute specification filed on March 17, 2023 has been entered.
The disclosure is objected to because Table 3 at p. 47 is illegible.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objection
Claims 1-3, 7, 9, and 15 are objected to because of the following informalities: The claims recite non-elected embodiments.
Claim 1 is objected to because of the following informality: duplicate “B cell receptor (BCR) complex should be deleted.
Claim 2 is objected to because of the following informalities: The claim recites non-elected embodiments CD22, CD95, BTLA, CD72, LAIR1, CD85j, LAG-3, PD1, TIGIT, CTLA4, TIM3, VISTA, any CD38, 2B4, CD5, 4-1BB, CD2, CD49b, ICOS, TIM1,OX40, CD357, and CD30.
Claim 3 is objected to because of the following informalities: The claim recites non-elected embodiments CD3, CD4, CD8, CD79b, CD19, CD20, CD138, CD95, CD93, CD69, CD30, PD-1,CD40, BCMA, GPRC5D, BTLA, LAG-3, CD70, PLD4, CD27, CD80, CD86, CD226, 4-1 BB, CD2, CD49b, ICOS, TIM1,OX40, CD357, and CD30.
Claim 7 is objected to because of the following informalities: The claim recites non-elected embodiments CD22, CD95, BTLA, CD72, LAIR1, CD65j, and LAG-3.
Claim 9 is objected to because of the following informalities: The claim recites non-elected embodiments CD138, CD30, CD95, CD93, BCMA, GPRC5D, PD-1, BTLA, LAG- 3, CD70 and PLD4.
Claim 15 is objected to because of the following informalities: CD3, CD4, CD8, CD69, CD30 and PD-1.
Claim Rejections - 35 USC § 112
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 2-4, 6, 7, 9, 15 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 applicant regards as the invention.
Claims 2-3, 7, 9, 15 are rejected on the judicially-created 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). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature.
In the instant case, claim 2 recites Markush groups of inhibitor receptors such as CD22, CD32b, CD95, BTLA, CD72, LAIR1, CD85j, LAG-3, PD1, TIGIT, CTLA4, TIM3, VISTA, CD38, 2B4, CD5, 4-1BB, CD2, CD49b, ICOS, TIM1,OX40, CD357, and CD30 to which the multi-specific binds.
Claim 3 recites Markush groups of markers such as CD3, CD4, CD8, CD79b, CD19, CD20, CD38, CD138, CD95, CD93, CD69, CD30, PD-1,CD40, BCMA, GPRC5D, BTLA, LAG-3, CD70, PLD4, CD27, CD80, CD86, CD226, 4-1 BB, CD2, CD49b, ICOS, TIM1,OX40, CD357, and CD30 to which the multi-specific binds.
Claim 7 recites Markush groups of inhibitor receptors of CD22, CD32b, CD95, BTLA, CD72, LAIR1, CD85j and LAG-3 to which the multi-specific binds.
Claim 9 recites Markush groups of targeting marker is selected from CD38, CD138, CD30, CD95, CD93, BCMA, GPRC5D, PD-1, BTLA, LAG- 3, CD70 and PLD4 to which the multi-specific binds.
Claim 15 recites Markush groups of targeting marker is selected from CD3, CD4, CD8, CD38, CD69, CD30 and PD-1.
However, the multi-specific antibodies that bind to an extracellular domain of distinct inhibitor receptor, e.g., CD32b and targeting maker, e.g., CD38 do share the same structure, e.g., heavy and light chain variable regions or the six CDRs, for binding to an extracellular domain of distinct inhibitor receptor, e.g., CD22, CD95, BTLA, CD72, LAIR1, CD85j, LAG-3, PD1, TIGIT, CTLA4, TIM3, VISTA, CD38, 2B4, CD5, 4-1BB, CD2, CD49b, ICOS, TIM1,OX40, CD357, and CD30 and targeting marker, e.g., CD3, CD4, CD8, CD79b, CD19, CD20, CD138, CD95, CD93, CD69, CD30, PD-1,CD40, BCMA, GPRC5D, BTLA, LAG-3, CD70, PLD4, CD27, CD80, CD86, CD226, 4-1 BB, CD2, CD49b, ICOS, TIM1,OX40, CD357, and CD30 above. Therefore, the members of the Markush groups of these claims do not share a substantial structural feature essential to their binding function specificity. Thus, the Markush groups of these claims are improper.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. 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).
Regarding claim 4, the metes and bounds of claim 4 are rendered vague and indefinite as recited in its entirety because the claim is referencing limitations that are not set forth in either an independent claim or a dependent claim. A claim should not depend on table 2 found in the specification for completeness but instead, should be able to stand alone.
Incorporation by reference to a specific 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) (citations omitted). MPEP 2173.05(s)
Regarding claim 6, the phrases “low amount” and “low potential” render the claim indefinite and vague because it is unclear what amount is considered “low”. One of ordinary skill in the art would not reasonably be apprised of the metes and bounds of the invention.
Claim rejections under - 35 U.S.C. 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 1-11, 15 and 17 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.
MPEP § 2163 lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. “Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP § 2163.
The U.S. Court of Appeals for the Federal Circuit recently reaffirmed, in an en banc decision, that the written description requirement for a genus may be satisfied either by (i) the disclosure of a representative number of species falling within the scope of the genus or (ii) structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus. Ariad Pharmaceuticals', Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350, 94 U.S.P.Q.2d 1161, 1171 (en banc) (Fed. Cir. 2010), citing Regents" of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568-69, 43 U.S.P.Q.2d 1398, 1406 (Fed. Cir. 1997) and AbbVie v. Janssen Biotech and Centocor Biologics (Fed. Cir. 2014).
Claim 1 encompasses any multi-specific antibody comprising at least two different antigen binding regions (ABR), a first ABR specifically that binds to an extracellular domain of any inhibitory receptor expressed on activated immune cells; and a second ABR that specifically binds to any targeting marker selected from a member of the T cell receptor (TCR) or B cell receptor (BCR) complex, a molecule associated with a member of the T cell receptor (TCR) or B cell receptor (BCR) complex, an activating co-receptor expressed on lymphocytes, or a subset-specific receptor.
Claim 2 encompasses the multi-specific antibody of claim 1, wherein the inhibitor receptor is selected from CD22, CD32b (elected species), CD95, BTLA, CD72, LAIR1, CD85j, LAG-3, PD1, TIGIT, CTLA4, TIM3, VISTA, any CD38, 2B4, CD5, 4-1BB, CD2, CD49b, ICOS, TIM1,OX40, CD357, and CD30.
Claim 3 encompasses the multi-specific antibody of claim 1, wherein the targeting marker is selected from CD3, CD4, CD8, CD79b, CD19, CD20, any CD38 (elected species), CD138, CD95, CD93, CD69, CD30, PD-1,CD40, BCMA, GPRC5D, BTLA, LAG-3, CD70, PLD4, CD27, CD80, CD86, CD226, 4-1 BB, CD2, CD49b, ICOS, TIM1,OX40, CD357, and CD30.
Claim 4 encompasses the multi-specific antibody of claim 1, wherein the antibody is comprised of at least one antibody variable domain from Table 2.
Claim 5 encompasses the multi-specific antibody of claim 1, wherein the antibody is any bi-specific antibody.
Claim 6 encompasses the bi-specific antibody of claim 5, wherein the antibodies are bivalent with a low amount of artificial mutations and low potential for immunogenicity.
Claim 7 encompasses the multi-specific antibody of claim 1, wherein the first ABR selectively binds to an inhibitory receptor selected from CD22, any CD32b (elected species), CD95, BTLA, CD72, LAIR1, CD85j and LAG-3.
Claim 8 encompasses the multi-specific antibody of claim 7, wherein the antibody specifically binds to the inhibitory receptor CD32b.
Claim 9 encompasses the multi-specific antibody of claim 7, wherein the targeting marker is selected from any CD38 (elected species), CD138, CD30, CD95, CD93, BCMA, GPRC5D, PD-1, BTLA, LAG- 3, CD70 and PLD4.
Claim 10 encompasses the multi-specific antibody of claim 1, wherein the targeting marker is any CD38.
Claim 15 encompasses the multi-specific antibody of claim 1, wherein the targeting marker is selected from CD3, CD4, CD8, any CD38 (elected species), CD69, CD30 and PD-1.
Claim 17 encompasses a pharmaceutical composition comprising a multi-specific antibody according to claim 1.
The specification discloses just one CD38 antibody comprising a heavy chain variable region of SEQ ID NO: 11 and a light chain variable region of SEQ ID NO: 12, see Table 2A. The specification discloses just one CD32b antibody comprising a heavy chain variable region of SEQ ID NO: 21 and a light chain variable region of SEQ ID NO: 22, see Table 2A.
However, specification does not describe i. Complete structure, e.g., amino acid sequences of heavy and light chains variable domains, ii. Partial structure, e.g., six CDRs of all multi-specific antibodies or bi-specific antibody comprising two or more different antigen binding regions (ABR), a first ABR specifically binds to any extracellular domain of any inhibitor receptor, such as CD32b on activated immune cells and any second AB that specifically binds to any targeting marker such as any CD38. The specification does not describe a representative number of species falling with the scope of the genus or structure common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed multi-specific antibodies or bi-specific antibodies themselves. Mere idea or binding function is insufficient for written description; isolation and characterization at a minimum are required. A description of what a material does, rather than what it is, usually does not suffice. Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
It is 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.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al (J Mol Biol. 334(1): 103-118, 2003; PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla et al (Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and a single species cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in Abbvie).
Regarding “low amount of artificial mutations” in claim 6, the term “mutations” encompasses substitution, deletion, addition and a combination thereof. The specification does not teach where and what within the full-length sequence of which heavy and light chain variable domains to be substituted, deleted, added or a combination thereof such that the modified antibody still maintains antigen binding. The specification does not teach where and what within the full-length sequence of which heavy and light chain variable domains to be substituted, deleted, added or a combination thereof such that modified antibody has low potential for immunogenicity. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus of multi-specific antibody or bi-specific antibody as broadly claimed.
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), "[claiming antibodies with specific properties, e.g., an antibody that binds to human TNF-a with A2 specificity, can result in a claim that does not meet written description even if the human TNF-a protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
"[A] sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus." Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A "representative number of species" means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780,1790 (Fed. Cir. 2014) ("The '128 and '485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the 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 to provide a "representative number" of species.
The "structural features common to the members of the genus" needed for one of skill in the art to 'visualize or recognize' the members of the genus takes into account the state of the art at the time of the invention. For antibodies, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor, 97 USPQ2d at 1875 ("[T]he application only provides amino acid sequence information (a molecular description of the antibody) for a single mouse variable region, i.e., the variable region that the mouse A2 antibody and the chimeric antibody have in common. However, the mouse variable region sequence does not serve as a stepping stone to identifying a human variable region within the scope of the claims."). A chimeric antibody shares the full heavy and light chain variable regions with the corresponding mouse antibody; that is, the structure shared between a mouse and chimeric antibody would generally be expected to conserve the antigen binding activity. Lastly, possession may not be shown by screening assays. Ariad, 94 USPQ2d at 1167; Centocor at 1876 ("The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.")
An adequate written description must contain enough information about the actual makeup of the claimed products - "a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials", which may be present in "functional terminology when the art has established a correlation between structure and function" (Amgen page 1361).
In Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), the court explained in Amgen that when an antibody is claimed, 35 U.S.C § 112(a) requires adequate written description of the antibody itself. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “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).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 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.
Therefore, only (1) a multispecific or bi-specific antibody comprising at least two different antigen binding regions (ABR), a first ABR that specifically binds to an extracellular domain of an inhibitor receptor of CD32b and a second ABR that specifically binds to CD38 on B cell, wherein the first binding regions (ABR) comprising a first heavy chain variable domain and a first light chain variable domain wherein the heavy chain variable domain consisting of the amino acid sequence of SEQ ID NO: 21 and the light chain variable region of SEQ ID NO: 22 and wherein the second ABR that specifically binds to CD38 comprising a heavy chain variable domain and a first light chain variable domain wherein the heavy chain variable domain consisting of the amino acid sequence of SEQ ID NO: 11 and the light chain variable domain consisting of the amino acid sequence of SEQ ID NO: 12, (2) a pharmaceutical composition comprising said multi-specific antibody or said bispecific antibody and a pharmaceutically acceptable carrier, but not the full breadth of the claims meets 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).
Claims 1-11, 15 and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for (1) a multispecific or bi-specific antibody comprising at least two different antigen binding regions (ABR), a first ABR that specifically binds to an extracellular domain of an inhibitor receptor of CD32b and a second ABR that specifically binds to CD38 on B cell, wherein the first binding regions (ABR) comprising a first heavy chain variable domain and a first light chain variable domain wherein the heavy chain variable domain consisting of the amino acid sequence of SEQ ID NO: 21 and the light chain variable region of SEQ ID NO: 22 and wherein the second ABR that specifically binds to CD38 comprising a heavy chain variable domain and a first light chain variable domain wherein the heavy chain variable domain consisting of the amino acid sequence of SEQ ID NO: 11 and the light chain variable domain consisting of the amino acid sequence of SEQ ID NO: 12, (2) a pharmaceutical composition comprising said multi-specific antibody or said bispecific antibody and a pharmaceutically acceptable carrier,, does not reasonably provide enablement for any multispecific antibody as set forth in claims 1-11, 15 and 17. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re wands, 858 F.2d 731, 737.8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 1 encompasses any multi-specific antibody comprising at least two different antigen binding regions (ABR), a first ABR specifically that binds to an extracellular domain of any inhibitory receptor expressed on activated immune cells; and a second ABR that specifically binds to any targeting marker selected from a member of the T cell receptor (TCR) or B cell receptor (BCR) complex, a molecule associated with a member of the T cell receptor (TCR) or B cell receptor (BCR) complex, an activating co-receptor expressed on lymphocytes, or a subset-specific receptor.
Claim 2 encompasses the multi-specific antibody of claim 1, wherein the inhibitor receptor is selected from CD22, CD32b (elected species), CD95, BTLA, CD72, LAIR1, CD85j, LAG-3, PD1, TIGIT, CTLA4, TIM3, VISTA, any CD38, 2B4, CD5, 4-1BB, CD2, CD49b, ICOS, TIM1,OX40, CD357, and CD30.
Claim 3 encompasses the multi-specific antibody of claim 1, wherein the targeting marker is selected from CD3, CD4, CD8, CD79b, CD19, CD20, any CD38 (elected species), CD138, CD95, CD93, CD69, CD30, PD-1,CD40, BCMA, GPRC5D, BTLA, LAG-3, CD70, PLD4, CD27, CD80, CD86, CD226, 4-1 BB, CD2, CD49b, ICOS, TIM1,OX40, CD357, and CD30.
Claim 4 encompasses the multi-specific antibody of claim 1, wherein the antibody is comprised of at least one antibody variable domain from Table 2.
Claim 5 encompasses the multi-specific antibody of claim 1, wherein the antibody is any bi-specific antibody.
Claim 6 encompasses the bi-specific antibody of claim 5, wherein the antibodies are bivalent with a low amount of artificial mutations and low potential for immunogenicity.
Claim 7 encompasses the multi-specific antibody of claim 1, wherein the first ABR selectively binds to an inhibitory receptor selected from CD22, any CD32b (elected species), CD95, BTLA, CD72, LAIR1, CD85j and LAG-3.
Claim 8 encompasses the multi-specific antibody of claim 7, wherein the antibody specifically binds to the inhibitory receptor CD32b.
Claim 9 encompasses the multi-specific antibody of claim 7, wherein the targeting marker is selected from any CD38 (elected species), CD138, CD30, CD95, CD93, BCMA, GPRC5D, PD-1, BTLA, LAG- 3, CD70 and PLD4.
Claim 10 encompasses the multi-specific antibody of claim 1, wherein the targeting marker is any CD38.
Claim 15 encompasses the multi-specific antibody of claim 1, wherein the targeting marker is selected from CD3, CD4, CD8, any CD38 (elected species), CD69, CD30 and PD-1.
Claim 17 encompasses a pharmaceutical composition comprising a multi-specific antibody according to claim 1.
The specification discloses just one CD38 antibody comprising a heavy chain variable region of SEQ ID NO: 11 and a light chain variable region of SEQ ID NO: 12, see Table 2A. The specification discloses just one CD32b antibody comprising a heavy chain variable region of SEQ ID NO: 21 and a light chain variable region of SEQ ID NO: 22, see Table 2A.
However, the specification does not teach i. Complete structure, e.g., amino acid sequences of heavy and light chains variable domains, ii. Partial structure, e.g., six CDRs of all multi-specific antibodies or bi-specific antibody comprising two or more different antigen binding regions (ABR), a first ABR specifically binds to any extracellular domain of any inhibitor receptor, such as CD32b on activated immune cells and any second AB that specifically binds to any targeting marker such as any CD38.
It is 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.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; see, e.g., Discussion).
Similarly, Edwards et al., J Mol Biol. 334(1): 103-118, 2003; PTO 892, found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla et al (Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen, and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen.
Regarding “low amount of artificial mutations” in claim 6, the term “mutations” encompasses substitution, deletion, addition and a combination thereof. The specification does not teach where and what within the full-length sequence of which heavy and light chain variable domains to be substituted, deleted, added or a combination thereof such that the modified antibody still maintains antigen binding and low potential for immunogenicity.
There are no working examples. It is unpredictable which undisclosed multispecific or bi-specific antibody is effective as a pharmaceutical composition for treating any and all inflammatory or autoimmune diseases, including but not limited to rheumatoid arthritis, myasthenia gravis, systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), psoriatic arthritis. As such, it would require undue experimentation of one skilled in the art to practice the claimed invention.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 2-3, 5, 7, 8 and 17 are rejected under 35 U.S.C. 102 (a)(1) or (a)(2) as being anticipated by Johnson et al (US20160194396, published July 7, 2016; PTO 892).
Regarding claims 1-3, 5, 7, 8, Johnson teaches bi-specific antibody (see para. [0184], [0389]) that binds to the extracellular domain (without interfering or impeding Fc binding) of CD32b and a B-cell receptor, e.g., CD79b, see entire document, para. [0031] to [0032], [0101].
Regarding claim 4, Johnson teaches that the light chain variable domain (VL) that binds to CD32b is SEQ ID NO: 22, which is 100% identical to the claimed SEQ ID NO: 11, see para. [0115], sequence alignment below:
Query Match 100.0%; Score 549; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCRASQEISGYLSWLQQKPGKAPRRLIYAASTLDSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRASQEISGYLSWLQQKPGKAPRRLIYAASTLDSGVPS 60
Qy 61 RFSGSESGTEFTLTISSLQPEDFATYYCLQYFSYPLTFGGGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSESGTEFTLTISSLQPEDFATYYCLQYFSYPLTFGGGTKVEIK 107
The heavy chain variable domain (VH) that binds to CD32b is SEQ ID NO: 12, which is identical to the claimed SEQ ID NO: 21, see para. [0116], sequence alignment below:
Query Match 100.0%; Score 611; Length 116;
Best Local Similarity 100.0%;
Matches 116; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDAWMDWVRQAPGKGLEWVAEIRNKAKNHAT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDAWMDWVRQAPGKGLEWVAEIRNKAKNHAT 60
Qy 61 YYAESVIGRFTISRDDAKNSLYLQMNSLRAEDTAVYYCGALGLDYWGQGTLVTVSS 116
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 YYAESVIGRFTISRDDAKNSLYLQMNSLRAEDTAVYYCGALGLDYWGQGTLVTVSS 116
The light chain variable domain (VL) that binds to CD79b is SEQ ID NO: 13, which is 100% identical to the claimed SEQ ID NO: 16, see para. [0117], sequence alignment below:
ALIGNMENT:
Query Match 100.0%; Score 590; Length 112;
Best Local Similarity 100.0%;
Matches 112; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWFQQRPGQSPNRLIYLVSKLD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWFQQRPGQSPNRLIYLVSKLD 60
Qy 61 SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPLTFGGGTKLEIK 112
||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPLTFGGGTKLEIK 112
And the heavy chain variable domain (VH) that binds to CD79b is SEQ ID NO: 14, which is identical to the claimed SEQ ID NO: 15, see para. [0119], sequence alignment below:
Query Match 100.0%; Score 602; Length 113;
Best Local Similarity 100.0%;
Matches 113; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMNWVRQAPGQGLEWIGMIDPSDSETHY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMNWVRQAPGQGLEWIGMIDPSDSETHY 60
Qy 61 NQKFKDRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARAMGYWGQGTTVTVSS 113
|||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NQKFKDRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARAMGYWGQGTTVTVSS 113
Regarding claim 17, Johnson teaches a pharmaceutical composition comprising such bi-specific antibody, see abstract, para. [0004], [0031], in particular.
Thus, the reference teachings anticipate the claimed invention.
Claims 1-3, 5-7, 8, 9, 10, 11, 15 and 17 are rejected under 35 U.S.C. 102 (a)(1) or (a)(2) as being anticipated by Balke et a (US20170198040, published July 13, 2017; PTO 892).
Regarding claims 1-3, 5, 7, 8, 9, 10, 11, 15, Balke teaches multispecific (see para. [0286]) or bispecific antibody (see para. [0028]) comprising a first antigen binding region, e.g., human CD32b-binding antibody or antigen-binding fragment thereof that binds to CD32b (aka FcγRIIb, inhibitory receptor, para. [0033], [0107]) and CD38 co-expressed on a B-cell, see para. [0029], [0032], [0034], [0286] to [0289], [0365] in particular.
Regarding claim 6, Balke teaches modifications have been made to framework residues within VH and/or VL, e.g., to improve the properties of the antibody, such as decrease the immunogenicity of the antibody, see para. [0337]. The antibody is bivalent comprising two Fab fragments linked by a disulfide bridge, see para. [0091] or diabodies which are bivalent, see para. [0290].
Regarding claim 17, Balke teaches a pharmaceutical composition comprising such bi-specific antibody, see abstract, para.[0031], [0085], in particular.
Thus, the reference teachings anticipate the claimed invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Johnson et al (US20160194396, published July 7, 2016; PTO 892) in view of Zhukovsky et al (WO2017162890, published September 28, 2017; PTO 892) and Balke et a (US20170198040, published July 13, 2017; PTO 892).
The teachings of Johnson have been discussed supra.
Regarding claim 4, Johnson teaches that the light chain variable domain (VL) that binds to CD32b is SEQ ID NO: 22, which is 100% identical to the claimed SEQ ID NO: 11, see para. [0115], sequence alignment below:
Query Match 100.0%; Score 549; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCRASQEISGYLSWLQQKPGKAPRRLIYAASTLDSGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCRASQEISGYLSWLQQKPGKAPRRLIYAASTLDSGVPS 60
Qy 61 RFSGSESGTEFTLTISSLQPEDFATYYCLQYFSYPLTFGGGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSESGTEFTLTISSLQPEDFATYYCLQYFSYPLTFGGGTKVEIK 107
The heavy chain variable domain (VH) that binds to CD32b is SEQ ID NO: 12, which is identical to the claimed SEQ ID NO: 21, see para. [0116], sequence alignment below:
Query Match 100.0%; Score 611; Length 116;
Best Local Similarity 100.0%;
Matches 116; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDAWMDWVRQAPGKGLEWVAEIRNKAKNHAT 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDAWMDWVRQAPGKGLEWVAEIRNKAKNHAT 60
Qy 61 YYAESVIGRFTISRDDAKNSLYLQMNSLRAEDTAVYYCGALGLDYWGQGTLVTVSS 116
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 YYAESVIGRFTISRDDAKNSLYLQMNSLRAEDTAVYYCGALGLDYWGQGTLVTVSS 116
The light chain variable domain (VL) that binds to CD79b is SEQ ID NO: 13, which is 100% identical to the claimed SEQ ID NO: 16, see para. [0117], sequence alignment below:
ALIGNMENT:
Query Match 100.0%; Score 590; Length 112;
Best Local Similarity 100.0%;
Matches 112; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWFQQRPGQSPNRLIYLVSKLD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWFQQRPGQSPNRLIYLVSKLD 60
Qy 61 SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPLTFGGGTKLEIK 112
||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPLTFGGGTKLEIK 112
And the heavy chain variable domain (VH) that binds to CD79b is SEQ ID NO: 14, which is identical to the claimed SEQ ID NO: 15, see para. [0119], sequence alignment below:
Query Match 100.0%; Score 602; Length 113;
Best Local Similarity 100.0%;
Matches 113; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMNWVRQAPGQGLEWIGMIDPSDSETHY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMNWVRQAPGQGLEWIGMIDPSDSETHY 60
Qy 61 NQKFKDRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARAMGYWGQGTTVTVSS 113
|||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NQKFKDRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARAMGYWGQGTTVTVSS 113
Johnson teaches that by cross-linking tumor and effector cells, the diabody not only brings the effector cell within the proximity of the tumor cells but leads to effective tumor killing, see para. [0026].
Johnson does not teach the light chain variable domain (VL) that binds to CD38 is SEQ ID NO: 11 and the heavy chain variable domain (VH) that binds to CD38 is SEQ ID NO: 12 as per claim 4.
However, Zhukovsky teaches that anti-CD38 antibody, daratumumab, has been approved for the treatment of patients with relapsed MM, see p. 1, in particular. Zhukovsky teaches that resistance of MM 20 tumor cells to antibody therapies is associated with the increased signaling of checkpoint inhibitor pathways (e.g.PD-1/PD-L1). Therefore, there is an opportunity to enhance cytotoxicity of anti-CD38 antibodies against MM tumor cells and simultaneously activate the immune system by inhibiting checkpoint inhibitor pathways (e.g. PD-1/PD-L1), see p. 1, line 21-23. Zhukovsky teaches that bispecific CD38/PD-L1 comprising anti-CD38 and anti-PD-L1 domain capable of simultaneously binding to both antigens, see entire document, p. 2, line 22-27, claims 1-7, in particular. The anti-CD38 binding domain comprises light chain variable domain (VL) and a heavy chain variable domain (VH) wherein the VL comprises the amino acid sequence of SEQ ID NO: 2, which is 100% identical to the claimed SEQ ID NO: 12, see p. 8, lines 1-11, sequence alignment below:
Query Match 100.0%; Score 556; Length 214;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA 60
Qy 61 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIK 107
And the reference VH comprises the amino acid sequence of SEQ ID NO: 22, which is 100% identical to the claimed SEQ ID NO: 11, see p. 8, line 33, sequence alignment below:
ALIGNMENT:
Query Match 100.0%; Score 643; Length 122;
Best Local Similarity 100.0%;
Matches 122; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYY 60
Qy 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTV 120
Qy 121 SS 122
||
Db 121 SS 122
Zhukovsky teaches that blocking antibodies targeting immune checkpoint pathways (anti-PD-1, anti-CTLA-4, anti-PD-L1, etc.) have demonstrated remarkable activity in different types of cancer (lung, melanoma etc.), see p. 1, lines 30-32. Therefore, specific targeting of anti-PD-L1 antibodies to the site of tumors (e.g. targeting CD38+ cancer cells) may help delivering anti-PD-L1 therapeutics to the site where immune stimulation is required, and may result in maximal immune cell stimulation allowing the complete blocking of PD-L1 on tumor and microenvironment cells. Such targeted immune cell activation at tumor sites may also reduce systemic activation of the immune cells, prevent adverse side effects, and permit higher dosing of therapeutic antibodies.
Balke teaches multispecific (see para. [0286]) or bispecific antibody (see para. [0028]) comprising a first antigen binding region, e.g., human CD32b-binding antibody or antigen-binding fragment thereof that binds to CD32b (aka FcyRIIb, inhibitory receptor, para. [0033], [0107]) and CD38 co-expressed on a B-cell, see para. [0029], [0032], [0034], [0286] to [0289], [0365] in particular. Balke teaches that the bispecific antibody binds a tumor antigen co-expressed with CD32b on a B-cell, see para. [0033]. The bispecific antibody is useful for treating CD32b-related condition such as B cell malignancies, Hodgkin’s lymphoma, Non-Hodgkin’s lymphoma, multiple myeloma, diffuse large B cell lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, small lymphocytic lymphoma, diffuse small cleaved cell lymphoma, MALT lymphoma, mantel cell lymphoma, marginal zone lymphoma, follicular lymphoma, or systemic light chain amyloidosis.
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to make a bispecific antibody