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 .
Status of the Claims
Claims 1 – 13, 15 – 21, 24, and 41 – 45 were pending. Claims 1, 4, 8, 16, 21 – 24 have been amended; claims 5 – 7 and 19 have been canceled; and claims 46 – 49 have been newly added. Claims 1 – 4, 8 – 13, 15 – 18, 20 – 21, 24 and 41 – 49 are currently pending, with claims 42 – 45 and 47 – 48 withdrawn from consideration as being drawn to non-elected species. Claims 1 – 4, 8 – 13, 15 – 18, 20 – 21, 24, 41, 46, and 49 are the subject of this Office Action.
Election/Restrictions
Applicant’s election without traverse of Group I, drawn to pharmaceutical compositions, antigen-binding protein constructs, and a kit in the reply filed on 09/04/2025 is acknowledged. Applicant also elects the species of an antibody having a heavy chain variable domain of SEQ ID NO: 227 and a light chain variable domain of SEQ ID NO: 189, without traverse.
Claims 1 – 4, 8 – 13, 15 – 18, 20 – 21, 24, 41 and 46 are examined on the merits.
WITHDRAWN OBJECTIONS/REJECTIONS
Nucleotide and/or Amino Acid Sequence Disclosures
The specification was objected to because the Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete.
In view of the amendments to the specification in the reply of 02/18/2026, this objection is withdrawn.
Double Patenting
Claims 1 – 4, 8 – 13, 15 – 18, 24, 41 and 46 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 3 – 4, 15 – 18, 20 – 21, 24, and 41 – 54 of copending Application No. 17/616,745 in view of SUTHERLAND and IGAWA.
In view of the claim amendments in the reply of 02/18/2026, this rejection is withdrawn.
Claims 1 – 4, 8 – 13, 15 – 18, 24, 41 and 46 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 – 4, 9 – 13, 15 – 21, 24, and 41 – 45 of copending Application No. 17/616,804 in view of SUTHERLAND and IGAWA.
In view of the claim amendments in the reply of 02/18/2026, this rejection is withdrawn.
REJECTIONS MAINTAINED IN MODIFIED FORM
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1 – 4, 9 – 13, 15 – 18, 20 – 21, 24, 41 and 46 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.
The following quotation from section 2163 of the Manual of Patent Examination Procedure (MPEP) is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirements for a generic claim covering several distinct inventions:
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice... 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 claimed genus... See BU Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
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.
Thus, when a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed.
Claims 1 – 4, 9 – 13, 15 – 21, 24, 41 and 46 are rejected as lacking adequate descriptive support for a possession of a generic ABPC. Independent claims 1, 4, 21 and 24 have been amended to include multiple alternatives for the heavy and light chain variable domains for the first antigen-binding domain that is capable of specifically binding CD33 or an epitope of CD33. For example, independent claim 1 recites that one set of alternatives for the heavy and light chain variable domains is “(a) a heavy chain variable domain comprising the heavy chain CDRs in SEQ ID NO: 1, wherein the heavy chain variable domain includes a histidine at one or more positions in SEQ ID NO: 1 from the group of: 26, 27, 29, 30, 31, 32, 33, 34, 50, 51, 52, 54, 55, 57, 58, 59, 60, 63, 64, 65, 66, 98, 100, 102, and 103, and a light chain variable domain comprising the light chain CDRs in SEQ ID NO: 2, wherein the light chain variable domain includes a histidine at one or more positions in SEQ ID NO: 2 from the group of: 28, 32, 33, 36, 38, 54, 55, 59, 94, 95, 96, 98, 100, and 101”. This results in a large variety of heavy and light chain variable domains for the first antigen binding site, all of which are not supported by the present specification.
The specification presents the names of several variants in the figures and in the Examples, such as variants of gemtuzumab. However, the number of variants is not commensurate in scope with the present claims. Furthermore, the structure of all the possible variants are not disclosed.
Furthermore, in Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the
Supreme Court, held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). See MPEP 2164.01.
Presently, the claimed antibody composition used is only defined by functional properties: its ability to bind CD33. Because multiple positions on the heavy and light chain variable domain can vary significantly, the structure of the first antigen-binding domain is not specific. For example, the ABPC of claim 1, 4, 21 or 24 can bind any epitope of CD33. In view of the fact patterns detailed in Amgen v. Sanofi, applicants are not in possession of such an ABPC which can bind to any epitope presented by the claimed ABPCs in claims 1 – 7, 9 – 13, 15 – 21, 24, 41 and 46.
Providing SEQ ID NOs for the ABPCs that represent specific sequences with each position of the sequence defined with a specific amino acid, such as a histidine, for claims 1 – 7, 9 – 13, 15 – 21, 24, 41 and 46 can provide sufficient structure(s) of the claimed antibodies or antibody fragments.
In view of this uncertainty and the lack of a representative number of examples of the claimed genus, the claims are rejected for lack of adequate written description support.
Response to Arguments
On p. 22, last paragraph – p. 23, first paragraph, of the reply of 02/18/2026, Applicant argues that “in view of the exemplary antigen-binding protein constructs described in present application, those skilled in the art would have understood that Applicant was in possession of the claimed antigen-binding protein constructs in each of the independent claims. Applicant has produced the following tables showing the antigen-binding protein constructs that meet the structural and functional limitations recited in each of the independent claims. Tables 1-3 shown below provide the details of the antigen-binding protein constructs recited in part (a) of each of independent claims 1, 4, 21, and 24. Tables 4-6 shown below provide the details of the antigen-binding protein constructs recited in part (b) of each of independent claims 1, 4, 21, and 24. Tables 7-9 shown below provide the details of the antigen- binding protein constructs recited in part (c) of each of independent claims 1, 4, 21, and 24. In each of Tables 1-9 shown below”.
Applicant’s arguments have been fully considered but not found persuasive because the number of possible structures that results from all the histidine(s) at any, some, or all the claimed positions in the heavy or light chain is not commensurate in scope with the examples in the present specification.
The specification supports the elected sequences of SEQ ID NOs: 189 and 227. However, according to present claim 1, the sequence of SEQ ID NO: 189 (light chain variable domain), for example, can have an amino acid replaced with histidine at one or more of 21 different positions. It is not clear which of the sequences in the specification or in the examples provided in the reply of 02/18/2026 represent the sequence of SEQ ID NO: 189 where one or more of 21 different positions have been replaced with histidine(s). Nonetheless, the examples provided by the applicant do not statistically cover all the possible structures that could result from SEQ ID NO: 189 with histidine(s) at one or more of 21 different positions. Furthermore, with the addition of the heavy chain variable domain that may also vary significantly with the substitution of amino acids at one or more positions, the possible number of structures for the first antigen-binding domain is vast.
Claims 1 – 4, 9 – 13, 15 – 18, 20 – 21, 24, 41 and 46 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 elected species SEQ ID NOs: 189 and 227, does not reasonably provide enablement for all the possible ABPCs resulting from the mutations recited in independent claims 1, 4, 21 and 24. 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.
Scope of Enablement
Claims 1 – 4, 9 – 13, 15 – 18, 20 – 21, 24, 41 and 46 are rejected under 35 U.S.C. 112(a) because, the claims recite that “the first antigen-binding domain comprises:(a) a heavy chain variable domain comprising the heavy chain CDRs in SEQ ID NO: 1, wherein the heavy chain variable domain includes a histidine at one or more positions in SEQ ID NO: 1 from the group of: 26, 27, 29, 30, 31, 32, 33, 34, 50, 51, 52, 54, 55, 57, 58, 59, 60, 63, 64, 65, 66, 98, 100, 102, and 103, and a light chain variable domain comprising the light chain CDRs in SEQ ID NO: 2, wherein the light chain variable domain includes a histidine at one or more positions in SEQ ID NO: 2 from the group of: 28, 32, 33, 36, 38, 54, 55, 59, 94, 95, 96, 98, 100, and 101;a heavy chain variable domain comprising the heavy chain CDRs in SEQ ID NO: 1,wherein the heavy chain variable domain includes a histidine at one or more positions in SEQ ID NO: 1 from the group of: 26, 27, 29, 30, 31, 32, 33, 34, 50, 51, 52, 54, 55, 57, 58, 59, 60, 63, 64, 65, 66, 98, 100, 102, and 103, and a light chain variable domain comprising the light chain CDRs in SEQ ID NO: 2; or a heavy chain variable domain comprising the heavy chain CDRs in SEQ ID NO: 1 and a light chain variable domain comprising the light chain CDRs in SEQ ID NO: 2, wherein the light chain variable domain includes a histidine at one or more positions in SEQ ID NO: 2 from the group of: 28, 32, 33, 36, 38, 54, 55, 59, 94, 95, 96, 98, 100, and 101;(b) a heavy chain variable domain comprising the heavy chain CDRs in SEQ ID NO: 100, wherein the heavy chain variable domain includes a histidine at one or more positions in SEQ ID NO: 100 from the group of: 27, 29, 33, 50, 52, 53, 55, 57, 59, 101, and 103, and a light chain variable domain comprising the light chain CDRs in SEQ ID NO: 101, wherein the light chain variable domain includes a histidine at one or more positions in SEQ ID NO: 101 from the group of: 28, 29, 31, 34, 38, 39, 56, 57, 96, 97, 98, 99, 100, and 101; a heavy chain variable domain comprising the heavy chain CDRs in SEQ ID NO: 100, wherein the heavy chain variable domain includes a histidine at one or more positions in SEQ ID NO: 100 from the group of: 27, 29, 33, 50, 52, 53, 55, 57, 59, 101, and 103, and a light chain variable domain comprising the light chain CDRs in SEQ ID NO: 101; or a heavy chain variable domain comprising the heavy chain CDRs in SEQ ID NO: 100 and a light chain variable domain comprising the light chain CDRs in SEQ ID NO: 101, wherein the light chain variable domain includes a histidine at one or more positions in SEQ ID NO: 101 from the group of: 28, 29, 31, 34, 38, 39, 56, 57, 96, 97, 98, 99, 100, and 101; or (c) a heavy chain variable domain comprising the heavy chain CDRs in SEQ ID NO: 188, wherein the heavy chain variable domain includes a histidine at one or more positions in SEQ ID NO: 188 from the group of: 27,29,31,32,34,50,51,52,53,55,98, 100, 101, 105,and 106, and a light chain variable domain comprising the light chain CDRs in SEQ ID NO: 189, wherein the light chain variable domain includes a histidine at one or more positions in SEQ ID NO: 189 from the group of: 24, 25, 27, 28, 29, 30, 31, 50, 51, 52, 53, 54, 55, 56, 89, 90, 92, 93, 94, 95, and 97;a heavy chain variable domain comprising the heavy chain CDRs in SEQ ID NO: 188, wherein the heavy chain variable domain includes a histidine at one or more positions in SEQ ID NO: 188 from the group of: 27,29,31,32,34,50,51,52,53,55,98, 100, 101, 105,and 106, and a light chain variable domain comprising the light chain CDRs in SEQ ID NO: 189; or a heavy chain variable domain comprising the heavy chain CDRs in SEQ ID NO: 188 and a light chain variable domain comprising the light chain CDRs in SEQ ID NO: 189, wherein the light chain variable domain includes a histidine at one or more positions in SEQ ID NO: 189 from the group of: 24, 25, 27, 28, 29, 30, 31, 50, 51, 52, 53, 54, 55, 56, 89, 90, 92, 93, 94, 95, and 97”, which reads on a large variety of possible structures for the first antigen-binding domains, which may include antigen-binding domains that are not capable of specifically binding CD33 or an epitope of CD33 presented on the surface of a target mammalian cell as claimed.
In this regard, the application disclosure and claims have been compared per the factors indicated in the decision In re Wands, 8 USPQ 2d 1400 (Fed. Cir., 1988) as to undue experimentation. The factors include:
1) the nature of the invention;2) the scope or breadth of the claims;3) the state of the prior art;4) the predictability or unpredictability of the art; 5) the relative skill of those skilled in the art; 6) the presence or absence of working examples; 7) the amount of direction or guidance presented and,8) the quantity of experimentation necessary.
The relevant factors are addressed below on the basis of comparison of the disclosure, the claims and the state of the prior art in the assessment of undue experimentation.
Scope or breadth of the claims:
Independent claims 1, 4, 21 and 24 have been amended to include alternatives to the heavy and light chain variable domains of the first antigen binding domain of an ABPC that is capable of specifically binding CD33 or an epitope of CD33, which results in a large variety of structures for the heavy and light chain variable domains. However, the present specification as originally filed lacks adequate guidance, direction, or discussion to apprise the skilled artisan of all the resulting ABPCs that are capable of specifically binding CD33 or an epitope of CD33. The specification states that “histidine residues play an important role in engineering pH-dependent binding proteins” (p. 243, EXAMPLES, first paragraph) but does not provide explanation regarding the location of the histidine modifications on the anti-CD33 ABPC sequences. For example, the anti-CD33 ABPC sequence of SEQ ID NOs: 189 (VL of vadastuximab) seems to be a sequence prior to histidine substitution, which, according to the claims and specification, may be modified with histidines at one or more positions without providing guidance on the exact position(s) of the modifications.
Degree of predictability or unpredictability in the art: As taught by IGAWA (Igawa, T. et al. pH-dependent antigen-binding antibodies as a novel therapeutic modality, Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Volume 1844, Issue 11, 2014, Pages 1943-1950; an IDS reference submitted 06/02/2023), “histidine-based engineering is a general approach for generating pH-dependent binding antibodies that demonstrate a recycling property. However, in some cases, a simultaneous loss of binding affinity at neutral pH may occur. Since the binding affinity at neutral pH is important for the biological activity of the antibody, this loss of binding affinity at neutral pH may need to be recovered by subsequent affinity maturation” (see p. 1948, left column, second paragraph). Thus, the level of unpredictability in the art is high.
Relative skill possessed by those in the art: In view of the state and complexity of the prior art, and the scope of the claims, which are drawn to ABPCs , the level of skill in the art is high and is at least that of a medical doctor or Ph.D. scientist with several years of experience in the fields of antibody or antibody engineering and/or immunotherapy.
Presence or absence of working examples: The specification does not provide examples that define the effects resulting from the substitution of each position claimed or any of the number of possible combination of positions claimed in the heavy and light chain variable domains of an ABPC sequence with histidine(s).
Amount of guidance or direction provided/Quantity of experimentation required: The specification only provides guidance regarding the sequences prior to the substitution with histidine(s) and does not include any direction on how to prepare sequences with histidine substitutions at any, some, or all position(s) of the claimed sequences that still function as claimed. In the absence of working examples, undue experimentation would be necessary to determine the structure and scope of those ABPCs (if any) that fall within the bounds of the claim.
In summary, the claims do not require specific sequences that include the histidines on the claimed ABPC but rather has provided an idea of where the histidines could possibly be, which could statistically result in structures that vary. Thus, the claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Response to Arguments
On p. 27, under “Enablement”, Applicant argues that “[a]s claims 5-7 and 19 have been cancelled, the enablement rejection as applied to these claims is moot. Applicant submits that, in view of the present amendments to each of independent claims 1, 4, 21, and 24, and the exemplary constructs disclosed and tested in the present application (see, the remarks on the written description rejection above), the enablement rejection as applied to claims 1-4, 9-13, 15-18, 20, 21, 24, and 41 should be withdrawn.”
However, as discussed above, independent claims 1, 4, 21 and 24 have been amended so that the heavy and light chain variable domains include a histidine at one or more positions, resulting in a large variety of structures that may not all bind CD33. Thus, the claimed ABPC is not enabled.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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 the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1 – 4, 8 – 13, 15 – 18, 24, 41, 46, and 49 are rejected under 35 U.S.C. 103 as being unpatentable over SUTHERLAND (US 2013/0309223 A1, published 11/21/2013; see PTO-892: Notice of References Cited of 09/30/2025) in view of IGAWA (Igawa, T. et al. pH-dependent antigen-binding antibodies as a novel therapeutic modality, Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Volume 1844, Issue 11, 2014, Pages 1943-1950; see IDS).
According to the present specification, “antibodies against CD33 are used as a starting template for introduction of additional mutations that allow engineering of pH-dependent binding to CD33 and i) enhanced endolysosomal accumulation of a conjugated toxin, as well as ii) enhanced CD33 recycling to the cell surface” (p. 243, EXAMPLES, first paragraph).
According to the present specification, an ABPC conjugate is an Antibody-Drug Conjugate (ADC) (p. 159 and p. 251).
SUTHERLAND is directed to murine, chimeric, and humanized antibodies that specifically bind to CD33 that are useful for treatment and diagnoses of various cancers as well as detecting CD33. See abstract. SUTHERLAND teaches a pharmaceutical composition comprising a humanized or chimeric antibody that specifically binds to the human CD33 protein. See SUTHERLAND’s claims 1 and 21.
SUTHERLAND discloses a sequence having 100% identity to the sequence of Applicant’s elected species of a light chain variable domain of SEQ ID NO: 189. SUTHERLAND’s SEQ ID NO: 8 is identical to present SEQ ID NO: 189 of claims 1, 4, 8, 21 and 24. See Appendix.
It appears that the sequence of Applicant’s elected species of a heavy chain variable domain of SEQ ID NO: 227 is derived from the sequence of SEQ ID NO: 188 of option (c) of independent claims 1, 4, 21 and 24 where the glutamic acid at position 101 of SEQ ID NO: 188 is substituted with histidine:
188 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDINWVRQAPGQGLEWIGWIYPGDGSTKY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
227 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDINWVRQAPGQGLEWIGWIYPGDGSTKY 60
188 61 NEKFKAKATLTADTSTSTAYMELRSLRSDDTAVYYCASGYEDAMDYWGQGTTVTVSS 117
|||||||||||||||||||||||||||||||||||||||| ||||||||||||||||
227 61 NEKFKAKATLTADTSTSTAYMELRSLRSDDTAVYYCASGYHDAMDYWGQGTTVTVSS 117.
Thus, although SEQ ID NO: 227 does not appear on the amended independent claims, it is examined on the merits as part of the Applicant’s elected species.
SUTHERLAND teaches the sequence of SEQ ID NO: 188. SUTHERLAND’s SEQ ID NO: 18 is identical to present SEQ ID NO: 188 of present claims 1, 4, 8, 21 and 24. See Appendix.
However SUTHERLAND does not expressly teach that one or more amino acid position(s) on the heavy or light chain variable domain is/are substituted with histidine(s).
IGAWA is a review that discusses the features, approaches, advantages, and challenges of developing a pH-dependent binding antibody as a novel therapeutic modality. IGAWA discloses a pH-dependent antigen-binding antibody that binds to an antigen in plasma at neutral pH and dissociates from the antigen in endosome at acidic pH. See abstract. IGAWA teaches that because of the pKa of the imidazole group, histidine residues are protonated at endosomal acidic pH, which results in destabilizing the antibody–antigen interaction either directly, with histidine residues involved in interacting with the antigen. See p. 1947, left column, last sentence.
Regarding claims 1, 4, 21, 24 and 46, because SUTHERLAND discloses an antibody that is capable of specifically binding CD33 or an epitope of CD33 that is useful for treatment of cancer and IGAWA teaches that recycling antibodies with pH-dependent antigen binding offer significant advantages over conventional antibodies by dissociating the antigens in endosomes and recycling free antibodies back to plasma (see 7. Conclusion, p. 1950, left column), it would have been obvious to one having ordinary skill in the art to engineer an anti-CD33 ABPC with a pH-dependent dissociation rate or KD by including histidine(s) in order to treat cancer more effectively. There would have been reasonable expectation of success considering that CD33 is a known target in the treatment of cancer and ABPCs with a pH-dependent dissociation rate or KD is known to confer advantageous properties in the deliverance of drugs to the cells as evidenced by the applied prior art.
Regarding claims 2, according to the present specification, “at least one polypeptide of any of the ABPCs described herein is conjugated to the toxin, the radioisotope, or the drug via a cleavable linker. . . the cleavable linker is cleaved on the ABPC once it is transported to the lysosome or late endosome by the target mammalian cell” and that “the conjugated toxin, radioisotope, or drug is released during lysosomal and/or late endosomal degradation of the ABPC” (p. 234, second – third paragraph under “Conjugation”). Thus, degradation of the ABPC is understood to be the cleaving of the ABPC to release the conjugated toxin, radioisotope, or drug. SUTHERLAND teaches a similar phenomenon.
SUTHERLAND discloses that a therapeutic agent can be attached to the antibody with a cleavable linker that is sensitive to cleavage in the intracellular environment of the anti-CD33-expressing cancer cell but is not substantially sensitive to the extracellular environment, such that the conjugate is cleaved from the antibody when it is internalized by the anti-CD33-expressing cancer cell (e.g., in the endosomal or, for example by virtue of pH sensitivity or protease sensitivity, in the lysosomal environment or in the caveolear environment). See paragraph 0096.
Regarding claim 3 and 24, SUTHERLAND discloses that anti-CD33 antibodies can be conjugated to cytotoxic moieties to form antibody-drug conjugates (ADCs). Particularly suitable moieties for conjugation to antibodies are cytotoxic agents (e.g., chemotherapeutic agents), prodrug converting enzymes, radioactive isotopes or compounds, or toxins (these moieties being collectively referred to as therapeutic agents or drugs). See paragraph 0094.
Regarding claims 4 and 9, SUTHERLAND discloses an increase in cytotoxicity of the anti-CD33 ADC compared to control ADC h00d-SGD-1910 or h00-SGD-1269. See FIG. 2 and paragraph 0017.
Regarding claims 8 and 49, SUTHERLAND discloses a sequence having 100% identity to the sequence of Applicant’s elected species of SEQ ID NO: 189. See Appendix. Because IGAWA teaches that substituting the amino acids of antibodies with histidines confers advantageous pH-dependent properties, it would have been obvious to one having ordinary skill in the art to modify SUTHERLAND’s antibody with a histidine to arrive to the sequence of SEQ ID NO: 227.
Regarding claim 10, IGAWA discloses successfully generating high-affinity recycling antibodies with nanomolar KD at pH 7.4 and simultaneously have sufficient pH dependency or large kd at acidic pH by using histidine-based engineering and affinity maturation in all the antibodies targeting various antigens tested to date (see p. 1949, right column, third paragraph), suggesting that IGAWA’s histidine-engineered antibodies have an increase in internalization and endolysosomal delivery (see p. 1944 Fig. 1 B).
Regarding claim 11, according to the present specification, “ABPCs described herein (e.g., upon administration to a subject) results in less (e.g., a 1% decrease to about a 99% decrease, or any of the subranges of this range described herein) of a reduction in the level of CD33 presented on the surface of the target cell as compared to a composition including the same amount of a control ABPC (e.g., any of the control ABPCs described herein)” (p. 158, third paragraph). IGAWA teaches that the recycling function of an antibody can inhibit degradation of an antigen and results in a high concentration (see p. 1944, left column, first paragraph), suggesting that IGAWA’s engineered, recycling antibody results in a higher concentration of its targeted antigen, which may be CD33. Thus, SUTHERLAND in view of IGAWA renders an anti-CD33 ABPC of present claim 11, with at least a 1% decrease of a reduction in the level of CD33, obvious.
Regarding claim 12, SUTHERLAND discloses that therapeutic agent can be attached to the antibody with a cleavable linker that is sensitive to cleavage in the intracellular environment of the anti-CD33-expressing cancer cell. See paragraph 0096.
Regarding claim 13, SUTHERLAND discloses that an anti-CD33 antibody can be conjugated to a cytotoxic agent such as a chemotherapeutic agent, or a toxin (e.g., a cytostatic or cytocidal agent. See paragraph 0094.
Regarding claims 15 and 16, SUTHERLAND discloses that the antibody may be a single chain antibodies in which heavy and light chain variable domains are linked through a spacer. See paragraph 0074.
Regarding claims 17 and 18, SUTHERLAND discloses that antibodies can be expressed as tetramers containing two light and two heavy chains, as separate heavy chains, light chains, as Fab, Fab′, F(ab′)2, and Fv. See paragraph 0074.
Regarding claim 20, SUTHERLAND discloses that the antibody sites or is bispecific. See paragraphs 0024 – 0025. Regarding claim 41, because SUTHERLAND discloses pharmaceutical composition comprising the anti-CD33 antibody (see claim 21) and a kit to perform an assay for CD33 (see paragraph 0136), it would have been obvious to produce a kit comprising at least one dose of the pharmaceutical composition of the claimed ABPC.
Response to Arguments
On p. 27, under “35 U.S.C. § 103” of the reply of 02/18/2026, Applicant argues that “Igawa does not mention CD33 at all. Sutherland describes an anti-CD33 antibody, but do not teach or suggest modifying any of SEQ ID NOs: 1, 2, 100, 101, 188, and 189 with histidine at any of the specific positions recited in the presently amended independent claims.”
Applicant’s argument is not persuasive because IGAWA is directed to a novel antibody-engineering technique that utilizes the pH-dependency to overcome the limitations of conventional therapeutic antibodies (see the abstract). Thus, IGAWA’s technique may be applied to any therapeutic antibody, such as SUTHERLAND’s anti-CD33 antibody.
On p. 28, second – third paragraphs, of the reply, Applicant argues that “Applicant submits that the obviousness rejection should be withdrawn as one skilled in the art would not have reasonably expected that the introduction of a histidine at any of the specific positions recited in the presently amended independent claims would result in an antigen-binding protein construct that both (1) retains binding to CD33 and (2) has a dissociation rate of the first antigen-binding domain at a pH of about 4.0 to about 6.5 that is faster than the dissociation rate at a pH of about 7.0 to about 8.0 or a dissociation constant (KD) of the first antigen-binding domain at a pH of about 4.0 to about 6.5 that is greater than the KD at a pH of about 7.0 to about 8.0.” and that “the obviousness rejection should be withdrawn as the presently claimed antibodies and antigen-binding antibody fragments provide for unexpected technical effects”.
However, IGAWA teaches the advantages a histidine mutagenesis approach (see abstract or p. 144, right column, second paragraph, for example). MPEP 2145 states that "[e]vidence pertaining to secondary considerations must be taken into account whenever it has been properly presented; however, it does not necessarily control the obviousness conclusion. See, e.g., Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372, 82 USPQ2d 1321, 1339 (Fed. Cir. 2007) ('the record establish[ed] such a strong case of obviousness' that allegedly unexpectedly superior results were ultimately insufficient to overcome obviousness conclusion); Leapfrog Enterprises Inc. v. Fisher-Price Inc., 485 F.3d 1157, 1162, 82 USPQ2d 1687, 1692 (Fed. Cir. 2007) ("given the strength of the prima facie obviousness showing, the evidence on secondary considerations was inadequate to overcome a final conclusion" of obviousness); and Newell Cos., Inc. v. Kenney Mfg. Co., 864 F.2d 757, 768, 9 USPQ2d 1417, 1426 (Fed. Cir. 1988)."
Conclusion
Claims 1 – 4, 8 – 13, 15 – 18, 20 – 21, 24, 41, 46 and 49 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any 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 Estella Gustilo whose telephone number is (703)756-1706. The examiner can normally be reached Monday - Friday 9:30 AM - 5:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ESTELLA M. GUSTILO/Examiner, Art Unit 1646
/PETER J REDDIG/Primary Examiner, Art Unit 1646
APPENDIX
Alignment with SEQ ID NO: 189
RESULT 1
BAY79354
(NOTE: this sequence has 32 duplicates in the database searched.
See complete list at the end of this report)
ID BAY79354 standard; protein; 107 AA.
XX
AC BAY79354;
XX
DT 16-JAN-2014 (first entry)
XX
DE Mutant anti-CD33 humanized antibody VL sequence (LG), SEQ ID 8.
XX
KW CD33; acute myelogenous leukemia; acute promyelocytic leukemia;
KW antibody therapy; b-cell acute lymphoblastic leukemia; cancer;
KW chronic myelocytic leukemia; cytostatic; humanized antibody;
KW light chain variable region; monoclonal antibody; multiple myeloma;
KW mutein; myelodysplastic syndrome; myeloproliferative disorder; sarcoma;
KW t-cell acute lymphoblastic leukemia; therapeutic.
XX
OS Mus sp.
OS Homo sapiens.
OS Chimeric.
OS Synthetic.
XX
FH Key Location/Qualifiers
FT Misc-difference 22
FT /note= "Thr substituted by Asn as a result of back
FT mutation"
FT Region 24..34
FT /label= CDR1
FT Misc-difference 46
FT /note= "Ser substituted by Thr as a result of back
FT mutation"
FT Region 50..56
FT /label= CDR2
FT Misc-difference 69
FT /note= "Thr substituted by Gln as a result of back
FT mutation"
FT Misc-difference 71
FT /note= "Phe substituted by Tyr as a result of back
FT mutation"
FT Region 89..97
FT /label= CDR3
XX
CC PN US2013309223-A1.
XX
CC PD 21-NOV-2013.
XX
CC PF 14-MAR-2013; 2013US-00804227.
XX
PR 18-MAY-2012; 2012US-0649110P.
XX
CC PA (SUTH/) SUTHERLAND M K.
CC PA (RYAN/) RYAN M.
CC PA (SUSS/) SUSSMAN D.
CC PA (BURK/) BURKE P.
CC PA (JEFF/) JEFFREY S.
XX
CC PI Sutherland MK, Ryan M, Sussman D, Burke P, Jeffrey S;
XX
DR WPI; 2013-V12610/78.
DR N-PSDB; BAY79384.
XX
CC PT New isolated 2H12 antibody that specifically binds to human cluster of
CC PT differentiation 33 (CD33) protein comprising three heavy chain and three
CC PT light chain complementarity determining regions, used to treat cancer
CC PT that expresses CD33.
XX
CC PS Claim 4; SEQ ID NO 8; 49pp; English.
XX
CC The present invention relates to a novel antibody capable of binding to
CC CD33 protein. The invention further relates to a nucleic acid encoding a
CC mature heavy chain variable region (VH) and/or a mature light chain
CC variable region (VL) of the antibody. The novel antibody of the invention
CC can be used for treating a patient having or at risk of having cancer
CC e.g., acute myeloid leukemia, myelodysplastic syndrome, acute
CC promyelocytic leukemia, chronic myelogenous leukemia, chronic
CC myelomonocytic leukemia, chronic myeloproliferative disorders, precursor
CC B-cell acute lymphoblastic leukemia, precursor T-cell acute lymphoblastic
CC leukemia, multiple myeloma, mast cell disease and myeloid sarcoma. The
CC present sequence is a mutant anti-CD33 humanized antibody VL sequence
CC derived from mouse monoclonal antibody (m2H12), used in the invention for
CC treating the above-mentioned diseases.
XX
SQ Sequence 107 AA;
Query Match 100.0%; Score 559; Length 107;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTINCKASQDINSYLSWFQQKPGKAPKTLIYRANRLVDGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTINCKASQDINSYLSWFQQKPGKAPKTLIYRANRLVDGVPS 60
Qy 61 RFSGSGSGQDYTLTISSLQPEDFATYYCLQYDEFPLTFGGGTKVEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGQDYTLTISSLQPEDFATYYCLQYDEFPLTFGGGTKVEIK 107
Alignment with SEQ ID NOs: 190 – 192
BAY79364
(NOTE: this sequence has 40 duplicates in the database searched.
See complete list at the end of this report)
ID BAY79364 standard; protein; 117 AA.
XX
AC BAY79364;
XX
DT 16-JAN-2014 (first entry)
XX
DE Mutant anti-CD33 humanized antibody VH sequence (HI), SEQ ID 18.
XX
KW CD33; acute myelogenous leukemia; acute promyelocytic leukemia;
KW antibody therapy; b-cell acute lymphoblastic leukemia; cancer;
KW chronic myelocytic leukemia; cytostatic; heavy chain variable region;
KW humanized antibody; monoclonal antibody; multiple myeloma; mutein;
KW myelodysplastic syndrome; myeloproliferative disorder; sarcoma;
KW t-cell acute lymphoblastic leukemia; therapeutic.
XX
OS Mus sp.
OS Homo sapiens.
OS Chimeric.
OS Synthetic.
XX
FH Key Location/Qualifiers
FT Region 31..35
FT /label= CDR1
FT Misc-difference 48
FT /note= "Met substituted by Ile as a result of back
FT mutation"
FT Region 50..66
FT /label= CDR2
FT Misc-difference 67
FT /note= "Arg substituted by Lys as a result of back
FT mutation"
FT Misc-difference 68
FT /note= "Val substituted by Ala as a result of back
FT mutation"
FT Misc-difference 70
FT /note= "Met substituted by Leu as a result of back
FT mutation"
FT Misc-difference 72
FT /note= "Thr substituted by Ala as a result of back
FT mutation"
FT Misc-difference 98
FT /note= "Arg substituted by Ser as a result of back
FT mutation"
FT Region 99..106
FT /label= CDR3
XX
CC PN US2013309223-A1.
XX
CC PD 21-NOV-2013.
XX
CC PF 14-MAR-2013; 2013US-00804227.
XX
PR 18-MAY-2012; 2012US-0649110P.
XX
CC PA (SUTH/) SUTHERLAND M K.
CC PA (RYAN/) RYAN M.
CC PA (SUSS/) SUSSMAN D.
CC PA (BURK/) BURKE P.
CC PA (JEFF/) JEFFREY S.
XX
CC PI Sutherland MK, Ryan M, Sussman D, Burke P, Jeffrey S;
XX
DR WPI; 2013-V12610/78.
DR N-PSDB; BAY79393.
XX
CC PT New isolated 2H12 antibody that specifically binds to human cluster of
CC PT differentiation 33 (CD33) protein comprising three heavy chain and three
CC PT light chain complementarity determining regions, used to treat cancer
CC PT that expresses CD33.
XX
CC PS Claim 4; SEQ ID NO 18; 49pp; English.
XX
CC The present invention relates to a novel antibody capable of binding to
CC CD33 protein. The invention further relates to a nucleic acid encoding a
CC mature heavy chain variable region (VH) and/or a mature light chain
CC variable region (VL) of the antibody. The novel antibody of the invention
CC can be used for treating a patient having or at risk of having cancer
CC e.g., acute myeloid leukemia, myelodysplastic syndrome, acute
CC promyelocytic leukemia, chronic myelogenous leukemia, chronic
CC myelomonocytic leukemia, chronic myeloproliferative disorders, precursor
CC B-cell acute lymphoblastic leukemia, precursor T-cell acute lymphoblastic
CC leukemia, multiple myeloma, mast cell disease and myeloid sarcoma. The
CC present sequence is a mutant anti-CD33 humanized antibody VH sequence
CC derived from mouse monoclonal antibody (m2H12), used in the invention for
CC treating the above-mentioned diseases.
XX
SQ Sequence 117 AA;
Query Match 88.4%; Score 186.6; Length 117;
Best Local Similarity 45.7%;
Matches 37; Conservative 0; Mismatches 0; Indels 44; Gaps 2;
Qy 1 GYTFTNYDIN--------------WIYPGDGSTKYNEKFKA------------------- 27
|||||||||| |||||||||||||||||
Db 26 GYTFTNYDINWVRQAPGQGLEWIGWIYPGDGSTKYNEKFKAKATLTADTSTSTAYMELRS 85
Qy 28 -----------ASGYEDAMDY 37
||||||||||
Db 86 LRSDDTAVYYCASGYEDAMDY 106
Alignment with SEQ ID NO: 188
BAY79364
(NOTE: this sequence has 46 duplicates in the database searched.
See complete list at the end of this report)
ID BAY79364 standard; protein; 117 AA.
XX
AC BAY79364;
XX
DT 16-JAN-2014 (first entry)
XX
DE Mutant anti-CD33 humanized antibody VH sequence (HI), SEQ ID 18.
XX
KW CD33; acute myelogenous leukemia; acute promyelocytic leukemia;
KW antibody therapy; b-cell acute lymphoblastic leukemia; cancer;
KW chronic myelocytic leukemia; cytostatic; heavy chain variable region;
KW humanized antibody; monoclonal antibody; multiple myeloma; mutein;
KW myelodysplastic syndrome; myeloproliferative disorder; sarcoma;
KW t-cell acute lymphoblastic leukemia; therapeutic.
XX
OS Mus sp.
OS Homo sapiens.
OS Chimeric.
OS Synthetic.
XX
FH Key Location/Qualifiers
FT Region 31..35
FT /label= CDR1
FT Misc-difference 48
FT /note= "Met substituted by Ile as a result of back
FT mutation"
FT Region 50..66
FT /label= CDR2
FT Misc-difference 67
FT /note= "Arg substituted by Lys as a result of back
FT mutation"
FT Misc-difference 68
FT /note= "Val substituted by Ala as a result of back
FT mutation"
FT Misc-difference 70
FT /note= "Met substituted by Leu as a result of back
FT mutation"
FT Misc-difference 72
FT /note= "Thr substituted by Ala as a result of back
FT mutation"
FT Misc-difference 98
FT /note= "Arg substituted by Ser as a result of back
FT mutation"
FT Region 99..106
FT /label= CDR3
XX
CC PN US2013309223-A1.
XX
CC PD 21-NOV-2013.
XX
CC PF 14-MAR-2013; 2013US-00804227.
XX
PR 18-MAY-2012; 2012US-0649110P.
XX
CC PA (SUTH/) SUTHERLAND M K.
CC PA (RYAN/) RYAN M.
CC PA (SUSS/) SUSSMAN D.
CC PA (BURK/) BURKE P.
CC PA (JEFF/) JEFFREY S.
XX
CC PI Sutherland MK, Ryan M, Sussman D, Burke P, Jeffrey S;
XX
DR WPI; 2013-V12610/78.
DR N-PSDB; BAY79393.
XX
CC PT New isolated 2H12 antibody that specifically binds to human cluster of
CC PT differentiation 33 (CD33) protein comprising three heavy chain and three
CC PT light chain complementarity determining regions, used to treat cancer
CC PT that expresses CD33.
XX
CC PS Claim 4; SEQ ID NO 18; 49pp; English.
XX
CC The present invention relates to a novel antibody capable of binding to
CC CD33 protein. The invention further relates to a nucleic acid encoding a
CC mature heavy chain variable region (VH) and/or a mature light chain
CC variable region (VL) of the antibody. The novel antibody of the invention
CC can be used for treating a patient having or at risk of having cancer
CC e.g., acute myeloid leukemia, myelodysplastic syndrome, acute
CC promyelocytic leukemia, chronic myelogenous leukemia, chronic
CC myelomonocytic leukemia, chronic myeloproliferative disorders, precursor
CC B-cell acute lymphoblastic leukemia, precursor T-cell acute lymphoblastic
CC leukemia, multiple myeloma, mast cell disease and myeloid sarcoma. The
CC present sequence is a mutant anti-CD33 humanized antibody VH sequence
CC derived from mouse monoclonal antibody (m2H12), used in the invention for
CC treating the above-mentioned diseases.
XX
SQ Sequence 117 AA;
Query Match 100.0%; Score 624; Length 117;
Best Local Similarity 100.0%;
Matches 117; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDINWVRQAPGQGLEWIGWIYPGDGSTKY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDINWVRQAPGQGLEWIGWIYPGDGSTKY 60
Qy 61 NEKFKAKATLTADTSTSTAYMELRSLRSDDTAVYYCASGYEDAMDYWGQGTTVTVSS 117
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NEKFKAKATLTADTSTSTAYMELRSLRSDDTAVYYCASGYEDAMDYWGQGTTVTVSS 117
Prosecution Insights