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 .
Claims 1-21 are pending and examined on the merits.
Claim Objections
Claims 12 and 14 are objected to because of the following informalities:
i) the structures
PNG
media_image1.png
125
377
media_image1.png
Greyscale
in clam 12 are blurry; and
(ii) the structure
PNG
media_image2.png
145
502
media_image2.png
Greyscale
in claim 14 is blurry.
Appropriate correction is required.
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 13, 18, 20 and 21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 18 and 20, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claims 13 and 21, it is unclear how the recitations of “preferably MMAE” and “preferably Merkel cell carcinoma” , respectively, influence the metes and bounds of the claims.
Claim 18 is vague and indefinite in the recitation of “doxorubicin and/or cyclophosphamide”. It is unclear in the case of “or” if the cyclophosphamide is selected to the exclusion of doxorubicin.
Claim 18 is vague and indefinite in the recitation of “etoposide and/or an antibody”. It is unclear in the case of “or” if the antibody is selected to the exclusion of etoposide.
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.
Claim 18 is 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 a composition comprising the antibody of claim 1 and an additional antibody used in anti-cancer immunotherapy, does not reasonably provide enablement for composition comprising the antibody of claim 1 and the chemotherapeutic drugs of docetaxel, doxorubicin, cyclophosphamide, lenalidomide, dexamethasone, carboplatin, and/or etoposide admixed in a composition comprising the antibody of claim 1 in a therapeutically effective amount. 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).
When given the broadest reasonable interpretation, claim 18 include a combination comprising both the antibody conjugate of claim 1 and docetaxel, doxorubicin, cyclophosphamide, lenalidomide, dexamethasone, carboplatin, and/or etoposide in the same composition. The specification fails to provide any objective evidence regarding the physical combination of the antibody conjugate with the small molecule drugs of docetaxel, doxorubicin, cyclophosphamide, lenalidomide, dexamethasone, carboplatin, and/or etoposide. Lowe et al (Advances in Protein Chemistry and Structural Biology, 2011, Vol. 84, pp. 41-61) teach that monoclonal antibodies are prone to protein degradation through aggregation which must be minimized because this leads to lower in vivo efficacy (pages 42-43, bridging sentence). Lowe et al teach that the most commonly used techniques to protect the antibody from degradation is controlling the formulation of the mAb by optimization of ionic strength, pH and the addition of excipients (page 43, lines 3-6). Lowe et al teach that antibodies are large multidomain proteins and the factors that contribute to stability versus the propensity to aggregate are complex and not fully understood (page 43, lines 1-3 of the first full paragraph). Lowe et al teach that there are significant difference in stability and aggregation propensity between antibodies related to the primary amino acid sequence of the Fab region and the particular antigen specificity of the monoclonal (page 43, lines 3-10 of the first full paragraph).
The specification fails to teach a mixture of any anti-CD56 ADC having a altered Fc with docetaxel, doxorubicin, cyclophosphamide, lenalidomide, dexamethasone, carboplatin, and/or etoposide. There is no objective evidence that addition of the small molecules to the nivolumab antibody would not cause aggregation and degradation of the antibody, because addition of the small molecules, would require different pharmaceutical carriers because small molecule drugs are hydrophobic whereas the antibody portion of the ADC is hydrophilic. This would alter the solubility of the ADC and be expected to cause aggregation. Thus, one of skill in the art would be subjected to undue experimentation without reasonable expectation of success in order to combine both of the antibody conjugate of claim 1 and docetaxel, doxorubicin, cyclophosphamide, lenalidomide, dexamethasone, carboplatin, and/or etoposide.in the same dosage.
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.
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.
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.
Claims 1-14, 17, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Joubert et al (WO2015/004400, reference of the IDS, filed 6/12/2023) as evidenced by US 10,307,488 (English Language Translation) in view of Miao et al (WO2013/173391), Liu (WO2018/107116) and Acchione et al (mAbs, 2012, Vol. 4, pp. 362-372), as evidenced by Hristodorov et al (Mol. Biotechnology., 2013, Vol. 53, pp. 326-335)..
Joubert et al teach antibody drug conjugates comprising linkers wherein the linker comprises a linker head and a linker body, and a method of preparing said linkers (abstract). Joubert et al teach that the antibody drug conjugates comprise a connection to an antibody, a polarity region, a trigger a suicide spacer and a drug (Figure 1). Joubert et al teach the linker 22 (columns 47-48) wherein the linker head is pyridine, having two branches terminate in Bromine, a polarity region and a Val-Cit dipeptide and a p-amino benzyl alcohol:
PNG
media_image3.png
150
422
media_image3.png
Greyscale
which meets the limitations of claim 12 for a conjugation head which is
PNG
media_image4.png
111
208
media_image4.png
Greyscale
, wherein m is 5; a cleavable linker which is
PNG
media_image5.png
171
155
media_image5.png
Greyscale
, and a spacer which is
PNG
media_image6.png
109
168
media_image6.png
Greyscale
.
Joubert et al teach that a preferred antibody of the conjugate includes anti-CD56 antibody (column 22, line 60) which meets that limitation of claim 12. Joubert et al teach a general procedure wherein a solution of the desired antibody is reduced by TCEP and the linker is added (column 50, lines 40-51). One of skill in the art would understand that the free thiol of the reduced antibody would react with the linker resulting in a substitution of the antibody thiol for the bromine. Joubert et al teach an example using the same linker but with an analogous linker head,
PNG
media_image7.png
169
375
media_image7.png
Greyscale
is reacted to form an
adduct with MMAE (columns 39-40, structure 9-MMAE):
PNG
media_image8.png
466
564
media_image8.png
Greyscale
which meets the limitation of claim 12 for the linker comprising
PNG
media_image9.png
164
159
media_image9.png
Greyscale
the spacer of
PNG
media_image10.png
95
168
media_image10.png
Greyscale
, and claim 13 for reaction with MMAE 6-(2,6-bis(bromomethyl)pyridine-4-yl)amido-N-hexanamide-valine-citrullline-p-aminobenzoyl
carbamate, reacted with the preferred anti-CD56 antibody. Joubert et al teach that after reduction with TCEP (tris(2-carboxyethyl)phosphine), 8 cysteine residues accessible, consequently numerous species with DAR from 0 to 8 and that the average DAR is approximately 4 with conventional modifications (column 4, lines 35-40 and Figure 13). Joubert et al teach that MALDI-TOF mass analysis confirms that the reaction mixture contains 89% of species resulting from grafting of 4 linkers of 6-(3,4-dibromomaleimido)hexanoic acid on the antibody and thus the grafting average is 4.0 (column 4, lines 41-50) which meet the limitation of n=4 in claim 12, wherein the antibody is an IgG antibody (column 4, line 55). Joubert does not specifically teach the derivation of linker 22 to form an adduct with MMAE, the resulting number for “n” for the DAR after conjugation of linker 22-MMAE to the TCEP reduced antibody, a method of treating a CD56+ cancer comprising administering the antibody-drug conjugate of claim 1, or the attenuation of antibody effector functions of ADCC or CDC, or mutation of the Fc region for suppression or elimination of glycosylation .
Miao et al teach an analogous antibody-linker-drug conjugate:
PNG
media_image11.png
157
740
media_image11.png
Greyscale
wherein, the linker head differs from the instant linker head, and wherein the carbon adjacent to the exocyclic secondary amine does not carry a carbonyl group (claim 6 of ‘127, column 117). Miao et al teach that drug-conjugates include a multifunctional linker providing a 2-5 atom bridge (column 4, lines 23-24). Miao et al teach that the structural integrity of an antibody can be compromised after opening disulfide bonds and attaching payloads to the exposed free thiols and the compositions and method disclosed provide conjugation through cysteine without decreased structural stability (column 4, lines 32-36). Miao et al teach a method of treating a patient with cancer comprising administering an active agent-conjugate as disclosed (column 11, lines 19-22), thus meeting the limitations of claim 19 for the treatment of cancer. Miao et a specifically teach the conjugation of the linkers with trastuzumab which is an IgG1 antibody, which also meets the limitation of claim 11 of an IgG antibody.
Acchione et al teach that the IgG1 format is the most commonly used mAb platform for ADCs (page 363, lines 22-24 under the heading of “Results”).
It would have been prima facie obvious at the time prior to the effective filing date to react the linker 22 of Joubert et al to form a linker-drug with MMAE and to react the linker-MMAE with the TCEP reduced anti-CD56 antibody to provide the conjugate with MMAE in claim 14, wherein n is 4 and m is equal to 5. One of skill in the art would have been motivated to do so because Miao et al formed an antibody conjugate with a highly similar linker attached to MMAE. Miao et al teach that the linker head provides a 2-5 atom bridge and prevents antibody destabilization after reduction and loading of payloads.
It would have been further prima facie obvious that the resulting product of compound 22 resulting from the conjugation of free thiols on the antibody with linker 22 would have on the order of 89% of the species having a grafting average of 4 because the reaction of the antibody with the TCEP would make 8 cysteines available for reaction (Figure 13 of Joubert et al) to the linker resulting in a DAR of 4. It would have been prima facie obvious to treat CD56+ cancers with a composition comprising the resulting anti-CD56 ADC because Miao et al teach method of treating cancer with the active agent conjugates. One of skill in the art would understand that the ADC would be administered in a composition comprising a pharmaceutically acceptable carrier to facilitate the infusion of a particular dosage into the patient.
Regarding claims 1-11, Liu teaches engineering of the Fc region of an ADC to reduce/abolish or eliminate Fc binding, thereby reducing , abolishing or elimination effector functions such as ADCC and CDC mediated by the Fc-FcR interaction (page 12, lines 24-28). Liu teaches mutations in the Fc to reduce binding to at least one Fc gamma receptor (page 12, lines 27-29). Liu teaches that the binding of an ADC to effector cells can reduce tumor localization , hinder internalization and lead to off-target toxicity (page 12, lines 23-24). Liu teaches reduced glycosylation imparts reduced effector functions of the antibody (page 52, lines 26-27). Liu teaches that the antibody may be engineered to an aglycosylated form (page 52, lines 18-20)). Liu teaches the N297A mutation which unexpectedly reduces off-target toxicity, provides increased half-life through improved pharmacokinetics, increased bioavailability, increased tolerability and favorable efficacy (page 13, lines 21-23). Liu teaches that mutation at position 297 reduces glycosylation of the antibody (page 5, lines 21-28). Hristodorov et al provide evidence that the N297A mutation provided a aglycosylated IgG1 (page 327 under the heading “Comparison of mAbs Treated with PNGase F by CGE” and page 329, Figure 2).
It would have been prima facie obvious at the time prior to the effective filing date to engineer the Fc region of the anti-CD56 antibody conjugate rendered obvious by the combined teachings of Joubert et al and Miao et al to produce the conjugate rendered obvious by the combined teachings of Joubert et al and Miao et, wherein the anti-CD56 antibody was an IgG antibody, and wherein the Fc region was engineered to have a N297A mutation, producing a aglycosylated antibody. One of skill in the art would have been motivated to do so because Liu teaches the N297A mutation which unexpectedly reduces off-target toxicity, provides increased half-life through improved pharmacokinetics, increased bioavailability, increased tolerability and favorable efficacy and Hristodorov et al provide evidence that the N297A mutation provided a aglycosylated IgG1, thus rendering obvious claims 2-10. Further Liu teaches engineering of the Fc region of an ADC to reduce/abolish or eliminate Fc binding, thereby reducing , abolishing or elimination effector functions such as ADCC and CDC mediated by the Fc-FcR interaction. Liu teaches that the binding of an ADC to effector cells can reduce tumor localization , hinder internalization and lead to off-target toxicity and that reduced glycosylation imparts reduced effector functions of the antibody. Thus, it would have been prima facie obvious at the time prior to the effective filing date to eliminate glycosylation by the N297A mutation such that ADCC and CDC were decreased. One of skill in the art would have been motivated to do so because Liu teaches that Fc effector functions lead to off-target toxicity and reduced tumor localization of the ADC due to interaction with cells expressing FcgR. One of skill ion the art would have been motivated to use a anti-CD56 for the ADC which was an IgG1 antibody. One of skill in the art would have been motivated to do so because Joubert et al teach ADC comprising IgG1, Miao et al teach analogous conjugated comprising trastuzumab which is an IgG1 antibody and Acchione et al teach that IgG1 is the most common platform for ADCs.
Claims 1-21 are rejected under 35 U.S.C. 103 as being unpatentable over Joubert et al as evidenced by US 10,307,488, Miao et al, Liu and Acchione et al as evidenced by Hristodorov et al as applied to claims 1-14, 17, and 19 above, and further in view of Dimitrov et al (WO2017/023780, reference of the IDS, filed 6/12/2023).
Claim 15 requires that A is m906.
Claim 16 specifies, in part, that the antibody drug conjugate of
PNG
media_image12.png
154
531
media_image12.png
Greyscale
Dimitrov et al teach a method of treating a subject having a CD56-positive cancer, comprising selecting a subject with a CD56-positive cancer and administering to the subject a therapeutically effective amount of the ADC of claim 1 (claim 28 of ‘568).wherein the CD56-positive cancer is a neuroblastoma, multiple myeloma, ovarian cancer, acute myeloid leukemia, Wilms tumor or small cell lung cancer (claim 30 of ‘568) which meets the limitations of claim 19 and claim 20 drawn to a myeloma and a hemopathy and claim 21 drawn to small cell lung cancer. Joubert et al and Miao et al teach that the m906 antibody comprises the variable heavy chain domain of SEQ ID NO: 6 (paragraph [0039]) and the variable light chain domain of SEQ ID NO: 8 (paragraph [0041]). Thus, claim 1 of ‘568 encompasses the m906 anti-CD56 antibody. Dimitrov et al teach that the antibodies of the invention can be administered as ADC and that any suitable anti-cancer agents can be administered in combination with the immunoconjugates (page 37, lines 26-28) such as cyclophosphamide (page 38, line 4]), etoposide (page 38, line 11) and docetaxel (page 38, line 25) which meets the limitations of claim 18.
It would have been prima facie obvious at the time of the effective filing date to use the m906 antibody and composition comprising the m906 antibody in combination with cyclophosphamide, etoposide or docetaxel of Dimitrov et al as the anti-CD56 antibody of Joubert et al. One of skill in the art would be motivated to do so because Dimitrov et al teaches that the m906 antibody is suitable for admisntration as an ADC, and cyclophosphamide, etoposide or docetaxel can be administered in combination with the immunoconjugate. It would have been prima facie obvious to use the ADC rendered obvious by the combined teachings of Joubert et al and Miao et al in a method of treating CD56+ cancers such as acute myeloid leukemia, and small cell lung cancer because Dimitrov et al teach m906 ADCs used for the treatment of these cancers. The combination of the ADC rendered obvious by the combined teachings of Joubert et al and Miao et al and the further teachings of the particular cancers to be treated with the ADCs as taught by Dimitrov et al in combination with cyclophosphamide, etoposide or docetaxel of Dimitrov et al renders obvious claims 10, 13, 17, 22, 24 and 25.
Dimitrov et al teach a method of treating a subject having a CD56-positive cancer, comprising selecting a subject with a CD56-positive cancer and administering to the subject a therapeutically effective amount of the ADC of claim 1 (claim 28 of ‘568).wherein the CD56-positive cancer is a neuroblastoma, multiple myeloma, ovarian cancer, acute myeloid leukemia, Wilms tumor or small cell lung cancer (claim 30 of ‘568) which meets the limitations of claim 12 and claim 20 drawn to a myeloma and a hemopathy and claim 21 drawn to acute myeloid leukemia. The CD56+ cancers which include small cell lung cancer meet the limitations of claim 13 and 22. Joubert et al and Miao et al teach that the m906 antibody comprises the variable heavy chain domain of SEQ ID NO: 6 (paragraph [0039]) and the variable light chain domain of SEQ ID NO: 8 (paragraph [0041]). Thus, claim 1 of ‘568 encompasses the m906 anti-CD56 antibody.. Dimitrov et al teach that the antibodies of the invention can be administered as ADC and that any suitable anti-cancer agents can be administered in combination with the immunoconjugates (page 37, lines 26-28) such as cyclophosphamide (page 38, line 4]), etoposide (page 38, line 11) and docetaxel (page 38, line 25) which meets the limitations of claim 10.
It would have been prima facie obvious at the time of the effective filing date to use the m906 antibody and composition comprising the m906 antibody in combination with cyclophosphamide, etoposide or docetaxel of Dimitrov et al as the anti-CD56 antibody of Joubert et al. One of skill in the art would be motivated to do so because Dimitrov et al teaches that the m906 antibody is suitable for admisntration as an ADC, and cyclophosphamide, etoposide or docetaxel can be administered in combination with the immunoconjugate. It would have been prima facie obvious to use the ADC rendered obvious by the combined teachings of Joubert et al and Miao et al in a method of treating CD56+ cancers such as acute myeloid leukemia, and small cell lung cancer because Dimitrov et al teach m906 ADCs used for the treatment of these cancers. The combination of the ADC rendered obvious by the combined teachings of Joubert et al and Miao et al and the further teachings of the particular cancers to be treated with the ADCs as taught by Dimitrov et al in combination with cyclophosphamide, etoposide or docetaxel of Dimitrov et al renders obvious claim 18-21.
Claims 1-21 are rejected under 35 U.S.C. 103 as being unpatentable over Joubert et al, Miao et al and Dimitrov et al as applied to claims 1-21 above, and further in view of Miller et al (‘Combining ADCs with Immuno-Oncology Agents’, In: Innovations for Next Generation Antibody-Drug Conjugates, Cancer Drug Discovery and Development, M. Damelin, ed., 2018, pp. 11-44).
Claim 18 recites that the composition of claim 17 further comprises an anti-PD-1 or anti-PD-L1 antibody.
Dimitrov et al teach that the antibodies of the invention can be administered as ADC and that any suitable anti-cancer agents can be administered in combination with the immunoconjugates (page 37, lines 26-28) including other antibodies which specifically target cancer cells (page 38, lines 1-2).
Miller et al teach the combination of cytotoxic payloads comprising auristatins with immune-oncology agents provide profound anti-tumor synergy (page 17, lines 4-12 under the heading “ADCs, Anti-Tumor Immunity and ICD), Miller et al list clinical trials of combined ADCs and Immuno-oncology agents, 15 of which use MMAE as the toxic payload in the ADC combined with the anti-PD-1 antibody and one of which uses MMAE as the toxic payload in the ADC combined with the anti-PD-L1 antibody (page 32, Table 1).
It would have been prima facie obvious at the time prior to the effective filing date to combine anti-PD-L1 antibody or anti-PD-1 antibody with the anti-CD56 ADC rendered obvious by the teachings of Joubert et al, Miao et al and Dimitrov et al. One of skill in the art would be motivated to use the anti-PD-L1 antibody because Dimitrov et al teach combinations of the ADC with other antibodies targeting cancer cells and Miller et al teach that it is used in combination with ADCs carrying MMAE as the cytotoxic payload. One of skill in the art would know that PD-L1 is expressed on tumor cells in the tumor microenvironment and thus it is an anti-body which targets cancer cells. One of skill in the art would also have been motivated to combine the ADC rendered obvious by the teachings of Joubert et al, Miao et al and Dimitrov et al with anti-PD-1. One of skill in the art would have been motivated to do so by the teachings of Miller et al on synergy between auristatins and immune-oncology drugs, and the further teachings of the clinical trials combining ADC comprising MMAE as the toxic payload with anti-PD-1 antibodies.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8, 10-13, 17-26 of copending Application No. 17/802,274 in view of Liu (WO2018/107116) and Acchione et al (mAbs, 2012, Vol. 4, pp. 362-372), as evidenced by Hristodorov et al (Mol. Biotechnology., 2013, Vol. 53, pp. 326-335)..
Claims 1-6, 8, 10-13, 17-26 of the ‘274 application teach the limitations of instant claims 11-21 with the exception of the anti-CD56 ADC having one or more effector functions mediated by the Fc attenuate, wherein the effector functions are ADCC and CDC, and wherein the Fc portion comprises a N297A mutation leading to an aglycosylated Fc.
Regarding instant claims 1-10, Liu teaches engineering of the Fc region of an ADC to reduce/abolish or eliminate Fc binding, thereby reducing , abolishing or elimination effector functions such as ADCC and CDC mediated by the Fc-FcR interaction (page 12, lines 24-28). Liu teaches mutations in the Fc to reduce binding to at least one Fc gamma receptor (page 12, lines 27-29). Liu teaches that the binding of an ADC to effector cells can reduce tumor localization , hinder internalization and lead to off-target toxicity (page 12, lines 23-24). Liu teaches reduced glycosylation imparts reduced effector functions of the antibody (page 52, lines 26-27). Liu teaches that the antibody may be engineered to an aglycosylated form (page 52, lines 18-20)). Liu teaches the N297A mutation which unexpectedly reduces off-target toxicity, provides increased half-life through improved pharmacokinetics, increased bioavailability, increased tolerability and favorable efficacy (page 13, lines 21-23). Liu teaches that mutation at position 297 reduces glycosylation of the antibody (page 5, lines 21-28). Hristodorov et al provide evidence that the N297A mutation provided a aglycosylated IgG1 (page 327 under the heading “Comparison of mAbs Treated with PNGase F by CGE” and page 329, Figure 2).
Regarding instant claim 11, Acchione et al teach that the IgG1 format is the most commonly used mAb platform for ADCs (page 363, lines 22-24 under the heading of “Results”).
It would have been prima facie obvious at the time prior to the effective filing date to engineer the Fc region of the anti-CD56 antibody conjugate of claims 1-6, 8, 10-13, 17-26 of the ‘274 application wherein the anti-CD56 antibody was an IgG antibody, and wherein the Fc region was engineered to have a N297A mutation, producing a aglycosylated antibody. One of skill in the art would have been motivated to do so because Liu teaches the N297A mutation which unexpectedly reduces off-target toxicity, provides increased half-life through improved pharmacokinetics, increased bioavailability, increased tolerability and favorable efficacy and Hristodorov et al provide evidence that the N297A mutation provided a aglycosylated IgG1, thus rendering obvious claims 2-10. Further Liu teaches engineering of the Fc region of an ADC to reduce/abolish or eliminate Fc binding, thereby reducing , abolishing or elimination effector functions such as ADCC and CDC mediated by the Fc-FcR interaction which renders obvious instant claim 1. Liu teaches that the binding of an ADC to effector cells can reduce tumor localization , hinder internalization and lead to off-target toxicity and that reduced glycosylation imparts reduced effector functions of the antibody. Thus, it would have been prima facie obvious at the time prior to the effective filing date to eliminate glycosylation by the N297A mutation such that ADCC and CDC were decreased. One of skill in the art would have been motivated to do so because Liu teaches that Fc effector functions lead to off-target toxicity and reduced tumor localization of the ADC due to interaction with cells expressing FcgR. One of skill ion the art would have been motivated to use an anti-CD56 for the ADC which was an IgG1 antibody. One of skill in the art would have been motivated to do so because, Acchione et al teach that IgG1 is the most common platform for ADCs.
This is a provisional nonstatutory double patenting rejection.
All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAREN A CANELLA whose telephone number is (571)272-0828. The examiner can normally be reached M-F 10-6:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/ Primary Examiner, Art Unit 1643
Prosecution Insights