DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
The preliminary amendment filed 5/17/2024 is acknowledged. Claims 3, 5-15, and 17-21 are amended. Claim 16 is cancelled. Claims 1-15 and 17-21 are pending and under examination.
Specification
The disclosure is objected to because of the following informalities: The specification p. 30 discloses the anti-DNA binding proteins DX1 and DX3 as having a VH domain comprising CDRs corresponding to SEQ ID NOs: 9, 10, and 11, and a VL domain comprising CDRs corresponding to SEQ ID NOs: 12, 13, and 14. This is incongruent with the specification p. 4-5 and attached sequence listing, which discloses SEQ ID NOs: 9 and 10 as full heavy and light chains, SEQ ID NO: 14 as a light chain variable region, SEQ ID NO: 11 as a light chain CDR, and SEQ ID NOs: 12 and 13 as heavy chain CDRs. To advance compact prosecution, the disclosed DX1 and DX3 antibodies are interpreted by the examiner to comprise SEQ ID NOs: 1-6 as this appears to be consistent with p. 4-5 of the specification and the attached sequence listing. Appropriate correction is required.
Claim Rejections - 35 USC § 112a
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 1-6, 9-15, and 17-21 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 written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see MPEP 2163(II)(3)(a)(i)(A), reduction to drawings MPEP 2163(II)(3)(a)(i)(B), 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 MPEP 2163(II)(3)(a)(i)(C).
Independent claims 1, 2, and 5 recite a method of delivering a payload to the brain using a cell-penetrating anti-DNA antibody defined by several alternative CDR sequences. The specification, discloses and characterizes two antibody species defined by a VH sequence set forth as SEQ ID NO: 7 and corresponding CDRs of SEQ ID NOs: 1-3, and a VL sequence set forth as SEQ ID NO: 8 and corresponding CDRs of SEQ ID NOs: 4- 6. The specification demonstrates brain uptake of radiolabeled or fluorescent imaging payloads of these two antibody species. Although the specification discloses additional VH and VL sequences and CDR combinations, it does not provide experimental data or other adequate disclosure demonstrating that the antibodies comprising the alterative CDR sequences possess, or would be expected to possess, the required functional properties, including anti-DNA binding, cell penetration, and blood-brain barrier transport. Antibody binding affinity, specificity, and biological function are known in the art to be highly sensitive to amino acid substitutions within CDRs, and such substitutions may significantly affect antigen binding and biological activity (see Rudikoff et al., abstract). Accordingly, the disclosure of multiple VH, VL, and CDR sequence alternatives, without corresponding experimental evidence or a demonstrated structure-function relationship supporting preservation of the recited functional properties across the full scope of the claimed variants, is insufficient to demonstrate possession of the claimed genus. Claims 3, 4, 6, 9-15, and 17-21 depend from these claims without limiting the species and are therefore included in this rejection.
Therefore, claims 1-6, 9-15, and 17-21 are rejected under 35 U.S.C. 112(a).
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.
Claims 5 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Campbell et al. (WO2019018428A1), in view of Liu et al. and in further view of Zhou et al.
The claims are drawn to a cell penetrating anti-DNA antibody drug conjugate (ADC).
Campbell et al. discloses cell penetrating anti-DNA binding proteins comprising defined variable heavy (VH) and variable light (VL) chain regions. In particular, Campbell et al. discloses a humanized Fv fragment comprising the amino acid sequence of SEQ ID NO: 41 [see claim 16]. SEQ ID NO: 41 comprises the VH and VL chain sequences corresponding to instant SEQ ID NOs: 7 and 8 [see alignment below], which comprise the CDR sequences of instant SEQ ID NOs: 1-6 (instant claims 1-3 and 5-8).
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWVSYISSGSSTIYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 133 EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWVSYISSGSSTIYY 192
Qy 61 ADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRGLLLDYWGQGTTVTVS----- 115
|||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 193 ADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARRGLLLDYWGQGTTVTVSSASTK 252
Qy 116 --------------SDIQMTQSPSSLSASLGDRATITCRASKTVSTSSYSYMHWYQQKPG 161
||||||||||||||||||||||||||||||||||||||||||||||
Db 253 GPSVFPLAPLESSGSDIQMTQSPSSLSASLGDRATITCRASKTVSTSSYSYMHWYQQKPG 312
Qy 162 QPPKLLIKYASYLESGVPSRFSGSGSGTDFTLTISSLQPEDAATYYCQHSREFPWTFGGG 221
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 313 QPPKLLIKYASYLESGVPSRFSGSGSGTDFTLTISSLQPEDAATYYCQHSREFPWTFGGG 372
Qy 222 TKVEIK 227
||||||
Db 373 TKVEIK 378
Accordingly, Campbell et al. discloses the claimed variable region of the instant application. Campbell et al. teaches that the disclosed antigen binding proteins may be incorporated into numerous binding protein formats, including intact antibodies comprising Fc domains [see p. 53, lines 20-23] (instant claims 1-3 and 5-8) and teaches that such antibodies may be IgG isotype [see p. 38, lines 28-29] (instant claims 1, 2, and 5). Campbell et al. teaches conjugation of the disclosed binding proteins to another compound [see claim 17], and specifically describes conjugation to therapeutic agents, including chemotherapeutic or anti-inflammatory agents (instant claim 9), as well as nucleic acids [see p. 44, lines 1-12] (instant claims 9, 10, 11, 12, and 20). Campbell et al. teaches conjugation of the disclosed binding proteins to diagnostic agents, including radioisotopes and detectable labels [see p. 44, lines 1-12] (instant claims 13 and 14). Thus, Campbell et al. teaches antibody and binding protein conjugates comprising a payload (instant claims 1, 2, 5, and 21). Campbell et al. teaches that the disclosed binding proteins are useful for delivering payloads [see p. 1, lines 9-13] (instant claims 1 and 2). Campbell et al. discloses intravenous administration of a humanized di-scFv comprising SEQ ID NO: 41 [see p. 58, example 2, Variant 13] in a mouse model of glioblastoma. Campbell et al. demonstrates that the humanized di-scFv crosses the blood-brain barrier (BBB), localizes within glioblastoma tissue, reduces tumor burden, and prolongs survival [see p. 60, example 5] (instant claims 2, 17, and 18). Similarly, Campbell et al. discloses a method of treating glioblastoma in a subject comprising administering the composition of claim 17, which is an Fv fragment comprising SEQ ID NO: 41 conjugated to another compound [see claim 26 and 34] (instant claims 2, 17 and 18). Campbell et al. discloses a subject to include humans [see p. 14, line 12] (instant claims 1, 2, and 15). Campbell et al. teaches that the disclosed proteins may also be used to treat a variety of conditions including cancer, tissue damage, injury, infection, or ischemia [see p. 49, lines 33-34] (instant claims 9, 10, 11, and 12).
Campbell et al. does not expressly disclose an intact humanized IgG antibody comprising the VH and VL regions of SEQ ID NO: 41 conjugated to a payload.
Liu et al. teaches that antibody variable domains may be reformatted from Fv fragments into larger antibody formats such as IgG antibodies, while maintaining binding affinity [see p. 436, col. 1, par. 2]. Additionally, Zhou et al. teaches that the full length 3E10 antibody, which is a naturally occurring cell penetrating anti-DNA antibody, as well as its FAB and scFV fragments, are each capable of mediating intracellular therapeutic cargo delivery while maintaining biological activity [see p. 1101, par. 3], demonstrating that the intracellular delivery properties of the 3E10 antigen binding domain are retained across multiple antibody formats even following attachment of a payload. Zhou et al. teaches that IgG antibodies are the predominant scaffold used for antibody therapeutic delivery [see p. 1096, par. 1, lines 6-8] (instant claims 5 and 6). Furthermore, Zhou et al. teaches successful treatment of non-cancer diseases, for example x-linked myotubular myopathy through intracellular delivery of a 3E10 myotubularin therapeutic [see p. 1101, par. 3].
It would have been obvious to a person having ordinary skill in the art to incorporate the variable regions disclosed as the humanized di-scFv or Fv fragment of Campbell et al. into the disclosed IgG antibody format and then conjugate the antibody with a therapeutic or diagnostic payload. Campbell et al. expressly teaches that the disclosed antigen-binding domains may be incorporated into intact antibodies, including IgG antibodies, and further teaches conjugation of the disclosed binding proteins to therapeutic and diagnostic compounds for delivery. Further, Liu et al. teaches that conversion from Fv fragments into longer formats could be done while maintaining affinity and specificity, and Zhou et al. teaches that full length cell penetrating anti-DNA 3E10 antibodies retain the intracellular delivery properties of the fragmented antigen binding domain and remain capable of delivering conjugated or fused therapeutic cargo while noting that IgG antibodies are the conventional scaffold for ADCs intended for therapeutic use. One would have reasonably expected that an IgG embodiment comprising the same antigen binding domains would retain the cell-penetrating and binding properties because the antigen-binding specificity of an antibody is primarily determined by its variable domains. Further, Liu et al. teaches that binding properties are maintained following reformatting into antibodies and attachment of a payload and Zhou et al. teaches that the full length 3E10 antibody, as well as FAB and scFV formats retain intracellular delivery capable of delivering cargo.
Therefore, claims 5 and 6 are rejected under 35 U.S.C. 103.
Claims 1, 3, 7-15, 20, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Campbell et al. (WO2019018428A1), in view of Liu et al., and in further view of Zhou et al. and Weisbart et al.
The claims are drawn a method of delivering a payload to the brain of a human subject without cancer.
The disclosure of Campbell et al., Liu et al., and Zhou et al. are discussed above and collectively teach the claimed antibody and conjugates.
The combination of these references does not teach or suggest that the antibody would cross the blood brain barrier in a human subject without cancer.
Weisbart et al. discloses intravenous administration of a 3E10 scFv-Hsp70 fusion protein in a model of ischemic stroke, which is a neurological disorder (instant claim 11), finding that the fusion protein penetrates ischemic brain tissue, reduces infarct volume, and improves neurological outcomes [see p. 4, par. 2, lines 8-12]. As such, Weisbart et al. teaches that 3E10 derived antigen binding domains are useful for delivering therapeutic payloads to brain tissue in non-cancer subjects.
It would have been obvious to administer a humanized IgG antibody comprising the anti-DNA antigen binding domains disclosed above, further conjugated to a therapeutic (which constitutes an ADC) (instant claim 21) or diagnostic payload, for the treatment of non-cancerous conditions in the brain because Campbell et al. teaches that the binding proteins function as cell-penetrating delivery vehicles for various diseases and Weisbart et al. further demonstrates that 3E10-derived molecules are capable of delivering therapeutic cargo to the brain for treatment of non-cancer conditions. Furthermore, Campbell et al. teaches that the payload may be anti-inflammatory agents, nucleic acids, imaging agents, or other compounds (instant claims 12-14). There would have been a reasonable expectation of success in making the claimed antibody as discussed above, and in using the claimed method given that the cell penetrating properties of anti-DNA antibodies such as 3E10 are associated with the binding domains and 3E10 derived molecules were demonstrated to retain their delivery capabilities when configured to different formats.
Therefore, claims 1, 3, 7-15, 20, and 21 are rejected under 35 U.S.C. 103.
Claims 2 and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Campbell et al. (WO2019018428A1), in view of Liu et al., and Zhou et al. and in further view of Patrys.
The claims are drawn a method of delivering a payload to the brain of a human subject with an intact blood brain barrier.
The disclosure of Campbell et al., Liu et al., and Zhou et al., are discussed above and collectively teach the claimed antibody and conjugates.
The combination of these references does not teach or suggest an expectation of success crossing the intact blood brain barrier of a human subject.
Patrys discloses that PAT-DX1, a humanized fragment of the 3E10 antibody, crosses the human BBB. Patrys discloses using a Transwell model of the human BBB comprising brain endothelial cells and astrocytes, where the binding protein passed the barrier while similarly sized molecules did not. Transport was reduced upon inhibition of ENT2, demonstrating that BBB penetration was mediated by the anti-DNA binding properties of the antibody [see p. 1, par. 3].
Accordingly, it would have been obvious to use the above anti-DNA antibody conjugated to a therapeutic drug or diagnostic in subjects with an intact BBB because the art teaches that the penetration abilities of the binding proteins are not limited to conditions in which the BBB is permeable (instant claim 2). Furthermore, it would have been obvious to administer the antibody drug conjugate to a subject with glioblastoma because Campbell et al. expressly teaches that the binding proteins can be used to treat such conditions. One would have expected success as the art teaches that the antibody drug conjugate can penetrate the intact blood brain barrier.
Therefore, claims 2, and 17-19 are rejected under 35 U.S.C. 103.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Tirone D Johnson whose telephone number is (571)272-1256. The examiner can normally be reached M-F, 9-5 ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at (571)272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/TIRONE D. JOHNSON/ Examiner, Art Unit 1675
/JEFFREY STUCKER/ Supervisory Patent Examiner, Art Unit 1675
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