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 .
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9/29/2025 has been entered.
Claim 1 has been amended. Claims 1, 3-4, 6-9, 13-14, 16, 17, 19, 20, 23, 24, 26, 28-30, 38, 39, 41, 43, 44, 46-48, 51, and 54-55 are now pending and currently under prosecution.
Maintained Rejection
(Arguments Addressed)
Claim Rejections - 35 USC § 103
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.
It is noted claim 1 recites a method “comprising” the recited steps. MPEP 2111.03 states: For the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004). In the instant case, the claims will be interpreted as methods that comprise any step and administration of reagents in addition to those recited in the claims.
It is noted that for claim 1 that recites a method that “consists essentially of” the recited steps, the phrase “consists essentially of” will be interpreted as comprising. MPEP 2111.03 states: For the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of” will be construed as equivalent to "comprising." In the instant case, the claims will be interpreted as methods that comprise any step and administration of reagents in addition to those recited in the claims.
Claim(s) 1, 4, 6-9, 13-14, 19, 20, 23, 46-48, 54, and 55 remain rejected under 35 U.S.C. 103 as being unpatentable over NCT03233347 (Record Version 4/30/2018), in view of NCT02505269 (Record History: 6/8/2018), Ansell et al (2017) (Nivolumab in the Treatment of Hogkin Lymphoma, Clin Cancer Res (2017) 23 (7): 1623–1626), Herrera et al (2018) (Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma, Blood (2018) 131 (11): 1183–1194), and Wang et al (US-10562977-B2; Published 1/5/2017).
NCT03233347 teaches a method for treating a hematologic cancer (stage I-II Hodgkin lymphoma) in a subject administering a therapy comprising an anti-CD30 antibody drug conjugate (Brentuximab Vedotin) and an anti-PD-1 antibody (nivolumab), doxorubicin and dacarbazine (administered in combination). NCT03233347 teaches that the anti-PD1 antibody is given after anti-CD30 antibody drug conjugate is given (anti-CD30 antibody drug conjugate is given over a span of 30 minutes), and that the anti-PD-1 antibody is given by intravenous infusion for a duration of approximately 60 minutes. NCT03233347 teaches that that the anti-CD30 antibody drug conjugate and the anti-PD-1 antibody are administered every 2 weeks, and that the anti-PD-1 antibody is administered beginning with cycle 1 of the administration of an anti-CD0 antibody drug conjugate. NCT03233347 teaches that the anti-CD30 antibody drug conjugate and the anti-PD-1 antibody are administered on days `1 and 15 of a 28-day cycle, and are administered for 4 cycles. [Brief Summary and Detailed Description] NCT03233347 teaches that the subject has not been previously treated. [Inclusion Criteria] NCT03233347 teaches that patients who received prior therapy with anti-PD-1, anti-PD-L1 or anti-PD-L2 therapy are excluded. [Exclusion criteria] NCT03233347 teaches that the anti-CD30 antibody is a monoclonal antibody and comprises monomethyl auristatin E. [Assigned Interventions, Drug: Brentuximab Vedotin] NCT03233347 teaches that drugs used in the chemotherapy, such as doxorubicin hydrochloride and dacarbazine, and brentuximab vedotin, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, and/or by stopping them from spreading. NCT03233347 teaches that targeted agent, such as nivolumab, may interfere with the ability of cancer cells to grow and spread by enhancing the immune system. NCT03233347 teaches that giving doxorubicin hydrochloride, dacarbazine, brentuximab vedotin, and nivolumab may improve survival of patients with stage I-II Hodgkin lymphoma. [Brief Summary]
However, NCT03233347: (1) does not describe that the method for treating hematologic cancer comprises anti-CD30 antibody drug conjugate, an anti-PD-1 antibody, doxorubicin, and dacarbazine, and that the anti-PD-1 antibody is administered at least 30 minutes after the anti-CD30 ADC, (2) that the anti-CD30 antibody of the anti-CD30 antibody drug conjugate comprises the instantly claimed sequences, or (3) that the hematologic cancer comprises one or more cells that express PD-L1 or PD-L2.
NCT02505269 teaches a method for treating hematologic cancer, Hodgkin lymphoma, comprising administering an anti-CD30 antibody drug conjugate, brentuximab, doxorubicin, and dacarbazine. NCT02505269 teaches that standard treatment, ABVD chemotherapy, leads to risks of secondary cancers, lung injury, heart injury among others. NCT02505269 teaches that this method eliminates the intensity of chemotherapy by administering targeted therapy, anti-CD30 antibody drug conjugate. [Study Description]
Ansell teaches a method of treating hematologic cancer, Hodgkin lymphoma, comprising administering nivolumab an anti-PD-1 antibody. Ansell teaches that Hodgkin Lymphoma has high expression of P-L1 and PD-L2 expression. [pg 1624] Ansell teaches that treatment of Hodgkin’s lymphoma with nivolumab demonstrates positive responses, including 17% complete responses. [pg 1624-1625]
Herrera teaches a method of treating hematologic cancer, Hodgkin lymphoma, comprising administering nivolumab and brentuximab vedotin. Herrera teaches that the brentuximab was administered 1.8 mg/kg IV for a 30-minute infusion and nivolumab was administered 3.0 mg/kg IV for 60-minute infusion. [pg 1184, Study Design and treatment] Herrera teaches that nivolumab (PD-1 inhibitor) is given at least 30 minutes after administration of brentuximab. [pg 1184, study design and treatment]
Herrera teaches that this combination was well tolerated and highly active, with overall response rate and complete response rate of 82% and 61%, respectively. [pg 1188] Herrera teaches that peripheral sensory neuropathy occurred in 15% of patients. [Table 3] Herrera teaches that the most common drug related grade 3 or 4 adverse events were neutropenia. [pg 1625, Adverse Events and Safety]
Wang teaches the instantly claimed sequences the anti-CD30 antibody are sequences of brentuximab vedotin. Wang teaches that the antibody can be used for the treatment of cancer, and that brentuximab vedotin is used for the treatment of Hodgkin lymphoma. (col. 1-2; see sequence alignments below)
Sequence Results:
Heavy Chain CDR: SEQ ID Nos: 4-6-8
US-15-113-610-6
Sequence 6, US/15113610
Patent No. 10562977
GENERAL INFORMATION
APPLICANT: SHANGHAI HENGRUI PHARMACEUTICAL CO. LTD.
APPLICANT: JIANGSU HENGRUI MEDICINE CO. LTD.
TITLE OF INVENTION: LIGAND-CYTOTOXIC DRUG CONJUGATE, PREPARATION METHOD THEREOF, AND
TITLE OF INVENTION: USES THEREOF
FILE REFERENCE: 688452-31US (750002CPUS)
CURRENT APPLICATION NUMBER: US/15/113,610
CURRENT FILING DATE: 2016-07-22
NUMBER OF SEQ ID NOS: 14
SEQ ID NO 6
LENGTH: 454
TYPE: PRT
ORGANISM: Artificial sequence
FEATURE:
OTHER INFORMATION: Heavy Chain of Brentuximab
Query Match 86.6%; Score 159.4; Length 454;
Best Local Similarity 39.5%;
Matches 30; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 DYYIT--------------WIYPGSGNTKYNEKFKG------------------------ 22
||||| |||||||||||||||||
Db 31 DYYITWVKQKPGQGLEWIGWIYPGSGNTKYNEKFKGKATLTVDTSSSTAFMQLSSLTSED 90
Qy 23 --------YGNYWFAY 30
||||||||
Light Chain CDR: SEQ ID Nos: 12-14-16
US-15-113-610-5
Filing date in PALM: 2016-07-22
Sequence 5, US/15113610
Patent No. 10562977
GENERAL INFORMATION
APPLICANT: SHANGHAI HENGRUI PHARMACEUTICAL CO. LTD.
APPLICANT: JIANGSU HENGRUI MEDICINE CO. LTD.
TITLE OF INVENTION: LIGAND-CYTOTOXIC DRUG CONJUGATE, PREPARATION METHOD THEREOF, AND
TITLE OF INVENTION: USES THEREOF
FILE REFERENCE: 688452-31US (750002CPUS)
CURRENT APPLICATION NUMBER: US/15/113,610
CURRENT FILING DATE: 2016-07-22
NUMBER OF SEQ ID NOS: 14
SEQ ID NO 5
LENGTH: 218
TYPE: PRT
ORGANISM: Artificial sequence
FEATURE:
OTHER INFORMATION: Light Chain of Brentuximab
%
Result Query Filing
No. Score Match Length ID Date Dups Description
-------------------------------------------------------------------------------------------------------------
6 138.3 84.8 218 US-15-028-005-11 2016-04-07 12 MODIFIED AMINO ACIDS COMPRISING TETRAZINE FUNCTIONAL GROUPS, METHODS OF PREPARAT
ALIGNMENT:
Query Match 84.8%; Score 138.3; Length 218;
Best Local Similarity 39.7%;
Matches 31; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy 1 KASQSVDFDGDSYMN---------------AASNLES----------------------- 22
||||||||||||||| |||||||
Db 24 KASQSVDFDGDSYMNWYQQKPGQPPKVLIYAASNLESGIPARFSGSGSGTDFTLNIHPVE 83
Qy 23 ---------QQSNEDPWT 31
|||||||||
Db 84 EEDAATYYCQQSNEDPWT 101
Heavy Chain Variable Region: SEQ ID No 2
US-15-113-610-6
Sequence 6, US/15113610
Patent No. 10562977
GENERAL INFORMATION
APPLICANT: SHANGHAI HENGRUI PHARMACEUTICAL CO. LTD.
APPLICANT: JIANGSU HENGRUI MEDICINE CO. LTD.
TITLE OF INVENTION: LIGAND-CYTOTOXIC DRUG CONJUGATE, PREPARATION METHOD THEREOF, AND
TITLE OF INVENTION: USES THEREOF
FILE REFERENCE: 688452-31US (750002CPUS)
CURRENT APPLICATION NUMBER: US/15/113,610
CURRENT FILING DATE: 2016-07-22
NUMBER OF SEQ ID NOS: 14
SEQ ID NO 6
LENGTH: 454
TYPE: PRT
ORGANISM: Artificial sequence
FEATURE:
OTHER INFORMATION: Heavy Chain of Brentuximab
Query Match 100.0%; Score 635; Length 454;
Best Local Similarity 100.0%;
Matches 117; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QIQLQQSGPEVVKPGASVKISCKASGYTFTDYYITWVKQKPGQGLEWIGWIYPGSGNTKY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QIQLQQSGPEVVKPGASVKISCKASGYTFTDYYITWVKQKPGQGLEWIGWIYPGSGNTKY 60
Qy 61 NEKFKGKATLTVDTSSSTAFMQLSSLTSEDTAVYFCANYGNYWFAYWGQGTQVTVSA 117
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NEKFKGKATLTVDTSSSTAFMQLSSLTSEDTAVYFCANYGNYWFAYWGQGTQVTVSA 117
Light Chain Variable Region: SEQ ID No 10
US-15-113-610-5
Filing date in PALM: 2016-07-22
Sequence 5, US/15113610
Patent No. 10562977
GENERAL INFORMATION
APPLICANT: SHANGHAI HENGRUI PHARMACEUTICAL CO. LTD.
APPLICANT: JIANGSU HENGRUI MEDICINE CO. LTD.
TITLE OF INVENTION: LIGAND-CYTOTOXIC DRUG CONJUGATE, PREPARATION METHOD THEREOF, AND
TITLE OF INVENTION: USES THEREOF
FILE REFERENCE: 688452-31US (750002CPUS)
CURRENT APPLICATION NUMBER: US/15/113,610
CURRENT FILING DATE: 2016-07-22
NUMBER OF SEQ ID NOS: 14
SEQ ID NO 5
LENGTH: 218
TYPE: PRT
ORGANISM: Artificial sequence
FEATURE:
OTHER INFORMATION: Light Chain of Brentuximab
ALIGNMENT:
Query Match 100.0%; Score 587; Length 218;
Best Local Similarity 100.0%;
Matches 111; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIVLTQSPASLAVSLGQRATISCKASQSVDFDGDSYMNWYQQKPGQPPKVLIYAASNLES 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIVLTQSPASLAVSLGQRATISCKASQSVDFDGDSYMNWYQQKPGQPPKVLIYAASNLES 60
Qy 61 GIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPWTFGGGTKLEIK 111
|||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPWTFGGGTKLEIK 111
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat hematologic cancer comprising administering a combination therapy comprising an anti-CD30 antibody drug conjugate, an anti-PD-1 antibody, doxorubicin and dacarbazine, and that the anti-PD-1 antibody is administered at least 30 minutes after administration of the anti-CD30 ADC. One would have been motivated to, because: (1) NCT03233347 teaches treatment of Hodgkin lymphoma comprising anti-CD30 antibody drug conjugate: brentuximab vedotin, an anti-PD-1 antibody: nivolumab, and chemotherapy that includes dacarbazine and doxorubicin, (2) NCT02505269 teaches treatment of Hodgkin lymphoma comprising administering brentuximab vedotin, doxorubicin, and dacarbazine, (3) Ansell teaches treatment of Hodgkin lymphoma comprising nivolumab, (5) Herrera teaches treatment of Hodgkin lymphoma comprising administering nivolumab and brentuximab and that nivolumab is administered at least 30 minutes after brentuximab, and (6) NCT02505269 teaches that standard chemotherapy, ABVD, leads to unwarranted risks to the patient. One of ordinary skill in the art would have a reasonable expectation of success, because: (1) NCT03233347 teaches that administering different drug with different mechanisms of action can improve survival of patients with Hodgkin lymphoma, (2) NCT02505269 teaches that limiting chemotherapy to doxorubicin and dacarbazine eliminates the intensity of chemotherapy when administering targeted therapy, and (6) Ansell teaches and demonstrates that the combination of nivolumab and brentuximab leads to positive clinical responses.
Those of skill in the art recognize that the four agents, an anti-CD30 antibody drug conjugate, an anti-PD-1 antibody, doxorubicin and dacarbazine, are all known to
to successfully, pharmaceutically treat hematologic cancer, Hodgkin lymphoma, could have been combined by known methods, and that in combination, each agent of the composition merely would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably treat hematologic cancer and have additive effects through the combination of the four agents.
As stated in the above rejection, each of these agents had been taught by the prior art to be effective treating hematologic cancer thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the four compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a composition which is to be used for the very same purpose of treating hematologic cancer, such as Hodgkin lymphoma.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute the anti-CD30 antibody of Wang in the method of NCT03233347. One would have been motivated to, and have a reasonable expectation of success, because: (1) NCT03233347 and NCT02505269 both teach the treatment of Hodgkin lymphoma comprising anti-CD30 antibody drug conjugate: brentuximab vedotin, and (2) Wang teaches that brentuximab vedotin is used for the treatment of Hodgkin lymphoma and teaches the instantly claimed sequences of brentuximab vedotin. One of skill in the art could have substituted one known bispecific anti-CD30 antibody for another, and the results of treatment of a hematologic cancer would have been predictable. [see MPEP 2144.06]
2144.06 Art Recognized Equivalence for the Same Purpose [R-08.2012]
I. COMBINING EQUIVALENTS KNOWN FOR THE SAME PURPOSE
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious).
II. SUBSTITUTING EQUIVALENTS KNOWN FOR THE SAME PURPOSE
In order to rely on equivalence as a rationale supporting an obviousness rejection, the equivalency must be recognized in the prior art, and cannot be based on applicant’s disclosure or the mere fact that the components at issue are functional or mechanical equivalents. In re Ruff, 256 F.2d 590, 118 USPQ 340 (CCPA 1958) (The mere fact that components are claimed as members of a Markush group cannot be relied upon to establish the equivalency of these components. However, an applicant’s expressed recognition of an art-recognized or obvious equivalent may be used to refute an argument that such equivalency does not exist.); Smith v. Hayashi, 209 USPQ 754 (Bd. of Pat. Inter. 1980) (The mere fact that phthalocyanine and selenium function as equivalent photoconductors in the claimed environment was not sufficient to establish that one would have been obvious over the other. However, there was evidence that both phthalocyanine and selenium were known photoconductors in the art of electrophotography. "This, in our view, presents strong evidence of obviousness in substituting one for the other in an electrophotographic environment as a photoconductor." 209 USPQ at 759.).
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An express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982).
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat hematologic cancer comprising one or more cells that express PD-L1 and/or PD-L2 in the method of NCT03233347. One would have been motivated to, and have a reasonable expectation of success, because: (1) the cited art all teach the agents treating Hodgkin lymphoma and (2) Ansell teaches that Hodgkin lymphoma has high expression of P-L1 and PD-L2 expression. Given the recognized need to treat Hodgkin lymphoma, and given the known fact that PD-L1 and PD-L2 are increased in Hodgkin lymphoma, one of skill in the art could have pursued treating a hematologic cancer in cells that express PD-L1 and/or PD-L2 in the method of NCT03233347, with a reasonable expectation of success.
Response to Arguments
Applicant argues that the Examiner has not established a prima facie case of obviousness as not all elements of the claims are disclosed or suggested in the cited art, and the art provides no motivation nor a reasonable expectation of success at arriving at the present invention. Applicant submits that the chemotherapeutic regimen recited in the claims consists essentially of doxorubicin and dacarbazine and therefore excludes use of other chemotherapeutics such as vinblastine.
Applicant cites the teachings of the prior art as the following:
NCT0323347 describes the use of brentuximab vedotin in combination with doxorubicin and dacarbazine (AD) to treat non-bulky stage Hodgkin lymphoma. NCT0323347 does not teach that nivolumab is given concurrent with the treatment regimen as recited in the present claims.
NCT02505269 does not teach or suggest any other combination therapy to treat hematologic cancers.
Ansell is cited for disclosure of treating Hodgkin lymphoma using nivolumab, (anti-PD1 antibody). Herrera is cited for disclosure of Hodgkin lymphoma using nivolumab in combination with brentuximab vedotin. Wang describes the sequences of the anti-CD30 antibody. Applicant argues that neither of these references suggest use of any other combination therapy to treat hematologic cancers.
Applicant argues that nothing in the combination of the cited art would have motivated one of ordinary skill to treat a hematologic cancer using the combination of anti-CD30 ADC plus anti-PD-1 antibody in combination with the limited chemotherapeutic regimen consisting essentially of doxorubicin and dacarbazine.
Applicants submit that the combination of therapeutic products is not predictable even when known products are combined for their intended purpose, and there is no expectation that such a new combination would provide additive effects of the different agents individually.
Applicant also points to post filing evidence describing the results of the Phase II study set out in the Examples to demonstrate that the claimed combination therapy resulted in complete response (CR) and objective response rates of 88% (95% confidence interval [Cl], 76.3-94.9) and 93% in patients with early-stage, classical Hodgkin lymphoma (Lee et al., Blood. 2025 Jan 16;145(3):290-299). These results would not have been predicted from the cited art when nothing in the combination of the disclosures describes results of any anti- PD- antibody + anti-CD30 ADC combination treatment with a chemotherapy regimen.
Applicant's arguments have been fully considered but they are not persuasive. With regards to the amendment to the claim to include the transitional term “consisting essentially of”, it is noted that this transitional will be interpreted as comprising. MPEP 2111.03 states: For the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of” will be construed as equivalent to "comprising."
The instant claims recite: “a method for treating a hematologic cancer in a subject comprising administering a therapy comprising an anti-CD30 antibody drug conjugate and an anti-PD-1 antibody, in combination with a chemotherapeutic regimen consisting essentially of doxorubicin and dacarbazine…”. “Consisting essentially of” will be interpreted as “comprising” as noted above, and may include any other step or chemotherapeutic agent, as it does not materially affect the basic and novel characteristics of the claimed invention. Thus, the claims will be interpreted as methods that comprise any step and administration of reagents in addition to those recited in the claims.
Applicants continue to argue individual references. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. It is the combination of all of the cited and relied upon references which made up the state of the art with regard to the claimed invention. Applicant's claimed invention fails to patentably distinguish over the state of the art represented by the cited references taken in combination. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, Applicants have argued and pointed out to the teachings of each individual reference and failed to consider the combined teachings to render the invention obvious.
As noted prior, the prior art was used for the following reasons:
NCT03233347 (the primary reference) teaches a method for treating a hematologic cancer (stage I-II Hodgkin lymphoma) in a subject administering a therapy comprising an anti-CD30 antibody drug conjugate (Brentuximab Vedotin) and an anti-PD-1 antibody (nivolumab), doxorubicin and dacarbazine (administered in combination). However, NCT03233347 does not describe that the method for treating hematologic cancer comprises anti-CD30 antibody drug conjugate, an anti-PD-1 antibody, doxorubicin, and dacarbazine. To remedy this deficiency, the Examiner relied on additional references in the 103 rejection, as secondary references, to further provide motivation and a reasonable expectation success, to be considered as a whole and not individually analyzed for the following reasons:
NCT02505269 teaches a method for treating hematologic cancer, Hodgkin lymphoma, comprising administering an anti-CD30 antibody drug conjugate, brentuximab, doxorubicin, and dacarbazine. This reference provides motivation as it teaches the agents and cancer treated. NCT02505269 also provides a reasonable expectation of success as it teaches that the method utilizing anti-CD30 antibody drug conjugate, doxorubicin, and dacarbazine, eliminates the intensity of chemotherapy by administering targeted therapy, anti-CD30 antibody drug conjugate.
Ansell teaches a method of treating Hodgkin lymphoma comprising administering nivolumab and teaches that nivolumab demonstrates positive responses, including 17% complete responses. The purpose of Ansell is to provide motivation to use nivolumab in hematologic cancers, and to demonstrate the success of this agent as it demonstrates 17% complete responses.
Herrera teaches a method of treating hematologic cancer, Hodgkin lymphoma, comprising administering nivolumab and brentuximab vedotin, and that nivolumab is administered at least 30 minutes after brentuximab. Herrera teaches that this combination was well tolerated and highly active, with overall response rate and complete response rate of 82% and 61%, respectively. Therefore, this provides motivation of utilizing nivolumab and brentuximab vedotin together and provides reasonable expectation of success as this combination is well tolerates and highly active.
Wang teaches the known instantly claimed sequences the anti-CD30 antibody are sequences of brentuximab vedotin, and teaches that this is used for Hodgkin lymphoma. The purpose of Wang is to demonstrate the known sequences of anti-CD30 antibody.
In summary, the primary reference, NCT03233347, provides motivation of the four agents (brentuximab vedotin, an anti-CD30 antibody), nivolumab (an anti-PD1, antibody), dacarbazine and doxorubicin. Although it teaches a fourth chemotherapeutic agent as well, this is not excluded from the claims. However, the Examiner relied on the additional secondary references to remedy this deficiency. The prior art provides motivation as: (1) NCT02505269 teaches treatment of Hodgkin lymphoma comprising administering brentuximab vedotin, doxorubicin, and dacarbazine, (2) Ansell teaches treatment of Hodgkin lymphoma comprising nivolumab, (3) Herrera teaches treatment of Hodgkin lymphoma comprising administering nivolumab and brentuximab, and (4) NCT02505269 teaches that standard chemotherapy, ABVD, leads to unwarranted risks to the patient. One would have a reasonable expectation of success because: (1) NCT03233347 teaches that administering different drug with different mechanisms of action can improve survival of patients with Hodgkin lymphoma, (2) NCT02505269 teaches that limiting chemotherapy to doxorubicin and dacarbazine eliminates the intensity of chemotherapy when administering targeted therapy, and (3) Ansell teaches and demonstrates that the combination of nivolumab and brentuximab leads to positive clinical responses.
Those of skill in the art recognize that the four agents, an anti-CD30 antibody drug conjugate, an anti-PD-1 antibody, doxorubicin and dacarbazine, are all known to
to successfully, pharmaceutically treat hematologic cancer, Hodgkin lymphoma, could have been combined by known methods, and that in combination, each agent of the composition merely would have performed the same function as they did separately, and one of ordinary skill in the art would have recognized that the results of the combination would predictably treat hematologic cancer and have additive effects through the combination of the four agents.
As stated in the above rejection, each of these agents had been taught by the prior art to be effective treating hematologic cancer thus the instant situation is amenable to the type of analysis set forth in In re Kerkhoven, 205 USPQ 1069 (CCPA 1980) wherein the court held that: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art.” In the instant case, it is prima facie obvious to combine the four compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a composition which is to be used for the very same purpose of treating hematologic cancer, such as Hodgkin lymphoma.
With regards to the post filing evidence describing the results of the Phase II study:
With regards to unexpected results, the MPEP states:
MPEP 716.02(d) states: Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the “objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.” In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at “elevated temperatures” using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C).
With regards to the post-filing evidence, the results of the phase 2 study of AN+AD in treatment naïve patients with hematologic cancer, also teaches that the 2-year PFS rate was 85% similar to what was observed in A+AVD in ECHELON-1. A+AVD, includes vinblastine instead of nivolumab. Lee et al teaches that the combination had improved efficacy, and that the combination without vinblastine and nivolumab instead results in well-tolerated safety profile. Thus, the results demonstrated in the post-filing evidence is not unexpected. Each of these agents are all known to treat hematologic cancers, whether administered alone, or in combination, as taught by the prior art above.
Therefore, one of skill in the art could have pursued treating hematologic cancer comprising administering the four agents based on the disclosure of the cited references. The combined references provide a reasonable expectation of success for their method to function in the treatment of treating hematologic cancer and contrary to arguments, the results argued for the combination therapy are expected.
Claim(s) 16, 17, 26, 28, 29, 30, 38, 39, 41, 43 and 44 remain rejected under 35 U.S.C. 103 as being unpatentable over NCT03233347 (Record Version 4/30/2018), NCT02505269 (Record History: 6/8/2018), Ansell et al (2017) (Nivolumab in the Treatment of Hogkin Lymphoma, Clin Cancer Res (2017) 23 (7): 1623–1626), Herrera et al (2018) (Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma, Blood (2018) 131 (11): 1183–1194); and Wang et al (US10562977 B2; Published 1/5/2017) (combined references) as applied to claims 1, 4, 6-9, 13-14, 16, 19, 20, 23, 46-48, 54, and 55 above, and further in view of FDA Package Insert: Brentuximab Vedotin, 11/2014, Renwick et al (Use of Filgrastim and Pegfilgrastim to Support Delivery of Chemotherapy. BioDrugs 23, 175–186, 2009), NCT03907488 (Record History: 4/8/2019), Ramchandren et al (Nivolumab for Newly Diagnosed Advanced-Stage Classif02c Hodgkin Lymphoma: Safety and Efficacy in the Phase II CheckMate 205 Study. J Clin Oncol. 2019 Aug 10;37(23):1997-2007), Batty et al (2012) (Doxorubicin, bleomycin, vinblastine and dacarbazine chemotherapy with interferon for advanced stage classic Hodgkin lymphoma: a 10-year follow-up study. Leukemia & Lymphoma, 53(5), 801–806), and Katz et al (Brentuximab Vedotin (SGN-35), Clin Cancer Res (2011) 17 (20): 6428–6436)
The teachings of the combined references are cited above, however, they do not teach: (1) that the method further comprises administering a granulopoiesis stimulating factor prophylactically, (2) to withhold administration of the anti-CD30 antibody drug conjugate if the subject exhibits Grade 3 or Grade 4 neuropathy, (3) the exact dosing of the anti-CD30 antibody drug conjugate, doxorubicin, dacarbazine, and nivolumab, or (4) that the antibody drug conjugate comprises MMAE and a protease cleavable linker.
The FDA Package Insert teaches the following regarding Brentuximab Vedotin:
It is indicated for treatment of patients with Hodgkin lymphoma and is administered as an infusion over 30 minutes [Section 1]
Doses can range between 1.2 mg/kg to 1.8 mg/kg [Section 2.1]
Dose Modification for patients experiencing peripheral neuropathy: dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg
Dose Modification for neutropenia: consider Granulocyte colony-stimulating factor (G-CSF) prophylaxis [Section 2.2]
Brentuximab vedotin is a CD30-directed antibody drug conjugate consisting of three components: 1) the chimeric IgG1 antibody cAC10, 2) microtubule tubule disrupting agent MMAE, and 3) a protease-cleavable linker that covalently attaches MMAE to Cac10. [SECTION 11]
Renwick teaches that neutropenia is a serious hematologic toxicity of myelosuppressive chemotherapy and that filgrastim, a recombinant human granulocyte colony-stimulating factor stimulates the production of neutrophils. Renwick teaches that filgrastim was proven to reduce the need for chemotherapy dose reductions and delays. [pg 176] Renwick teaches that filgrastim given 300 mcg/day was safe for patients. [pg 178] and doses can be given at a dose of 5 mcg/kg/day as well. [pg 179]
NCT03907488 teaches the treatment of Hodgkin Lymphoma comprising administering Brentuximab Vedotin plus chemotherapy. NCT03907488 teaches that patients may receive peg-filgrastim on days 2 and 16 or filgrastim IV on days 5-10. [Detailed Description] NCT03907488 teaches that patient must not have had an prior antibody-based treatment.
Ramchandren teaches a method of treating Hodgkin Lymphoma comprising administering nivolumab 240 mg IV and chemotherapy including doxorubicin and dacarbazine. [Whole document]
Batty teaches a method of treating Hodgkin Lymphoma comprising administering chemotherapy, doxorubicin and dacarbazine. Batty teaches that the doses administered are doxorubicin 25 mg/m2 and dacarbazine 375 mg/m2. [pg 802, Study Design]
Katz teaches that Brentuximab vedotin (SGN-35) is an antibody-drug conjugate (ADC) directed against the CD30 antigen expressed on Hodgkin lymphoma. [Introduction] Katz teaches that Brentuximab vedotin consists of the cAC10 monoclonal antibody modified by the addition of a dipeptide linker to permit attachment of microtubule polymerization monomethylauristatin E (MMAE) and that the protease-sensitive dipeptide linker is composed of citrulline and valine. Katz teaches that the advantage of the dipeptide linker is that it provides maximal serum stability with efficient hydrolysis and release of MMAE by human cathepsin B (Fig. 2A, see image below)
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It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer a granulopoiesis stimulating factor prophylactically after administration of an anti-CD30 antibody drug conjugate. One would have been motivated to, because: (1) Herrera teaches that the most common adverse events following treatment of an anti-CD30 antibody drug conjugate and an anti-PD-1 therapy is neutropenia, (2) the FDA Package Insert teaches that neutropenia is a common side effect and states to consider administering a granulocyte colony stimulating factor prophylactically, and (3) Renwick teaches that neutropenia is a serious hematologic toxicity associated with chemotherapy. One of ordinary skill in the art would have a reasonable expectation of success, because (1) NCT03907488 teaches administering filgrastim after administering chemotherapy and an anti-CD30 antibody drug conjugate, (3) Renwick teaches that doses of filgrastim 300 mcg/kg or 5 mcg/kg/day have been demonstrated to e safe and effective. Given the recognized need to prevent neutropenia, known side effects of neutropenia associated with chemotherapy and the anti-CD30 antibody drug conjugate, and given the known method and doses of administering a granulopoiesis stimulating factor after administration of an anti-CD30 antibody drug conjugate, one of skill in the art could have pursued administering a granulopoiesis stimulating factor after administration of an anti-CD30 antibody drug conjugate, with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to withhold an anti-CD30 antibody drug conjugate when a subject exhibits Grade 3 or Grade 4 neuropathy, until it decreases to Grade 2 or less and then administer the antibody at a lower concentration. One would have been motivated to, and have a reasonable expectation of success, because: (1) Herrera teaches that a common adverse event following treatment of an anti-CD30 antibody drug conjugate is neuropathy, (2) the FDA Package Insert teaches that neuropathy is a common side effect and states to withhold when patients are experiencing it until it improves and then restarting at a lower dose. Given recognized need to treat neuropathy associated with cancer-treatment medications, known side effects of neuropathy associated with the anti-CD30 antibody drug conjugate, and given the known method of withholding the antibody and restarting at a lower dose, one of skill in the art could have pursued withholding an anti-CD30 antibody drug conjugate when a subject exhibits Grade 3 or Grade 4 neuropathy, until it decreases to Grade 2 or less and then administer the antibody at a lower concentration. with a reasonable expectation of success.
It would have been prima facie obvious to one of the ordinary skill in the art at the time the invention was filed to treat a hematologic cancer comprising administering a CD30-antibody drug conjugate, brentuximab vedotin, at a dose of 1.2 mg/kg, an anti-PD-1 antibody, nivolumab, at a dose of 240 mg, doxorubicin at a dose of 25 mg/m2 and dacarbazine at a dose of 375 mg/m2. One would have been motivated to, and have a reasonable expectation of success, because (1) the cited references teach treating a hematologic cancer comprising administering the above agents, (2) the FDA package Insert of brentuximab vedotin teaches a dose of 1.2 mg/kg for treatment of Hodgkin lymphoma, (3) Ramchandren teaches and demonstrates a method of treating Hodgkin Lymphoma comprising administering nivolumab 240 mg, (4) Batty teaches and demonstrates a method of treating Hodgkin Lymphoma comprising administering doxorubicin 25 mg/m2 and dacarbazine 375 mg/m2. Given the recognized need to treat cancer, given known functions of the agents and the known doses used for treatment, and given the known successes as demonstrated by the prior art, one of skill in the art could have pursued administering the agents at the instantly claime ddoses, with a reasonable expectation of success.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to utilize the anti-CD30 antibody of Katz that includes MMAE and a protease cleavable linker, in the method of NCT03233347. One would have been motivated to, and have a reasonable expectation of success, because: (1) NCT03233347 and NCT02505269 both teach the treatment of Hodgkin lymphoma comprising anti-CD30 antibody drug conjugate: brentuximab vedotin, (2) NCT03233347 teaches that brentuximab comprises MMAE, (3) FDA Package Insert teaches that Brentuximab vedotin is a CD30-directed antibody drug conjugate consisting of three components: 1) the chimeric IgG1 antibody cAC10, 2) microtubule tubule disrupting agent MMAE, and 3) a protease-cleavable linker that covalently attaches MMAE to Cac10, (4) Katz teaches that brentuximab vedotin is used for the treatment of Hodgkin lymphoma and teaches the structure of brentuximab that includes a protease cleavable linker with a thioreactive spacer and dipeptide, and (5) Katz teaches that the advantage of the dipeptide linker is that it provides maximal serum stability with efficient hydrolysis and release of MMAE by human cathepsin B.
Response to Arguments
Applicant’s argue the claims are not obvious over the combination of NCT03233347, NCT02505269, Ansell, Herrara and Wang and the disclosure in FDA Package Insert, Renwick, Ramchandren, Batty and Katz do not remedy the deficiencies of the other cited art. Applicants argue that none of FDA Package Insert, Renwick, Ramchandren, Batty and Katz alone or in combination disclose or suggest a combination treatment method using brentuximab vedotin and another chemotherapeutic to treat hematologic cancers. Applicants argue that nothing in the combination of cited art would have motivated one of skill to arrive at the present combination treatment, or had a reasonable expectation of success that the treatment would provide such benefits as described in Lee et al (supra) for the reasons set out in Section IV above.
Applicant's arguments have been fully considered but they are not persuasive. As noted above, Applicant’s are arguing individual references and not considering all the references a whole. Examiner points to above arguments.
Claim(s) 24 and 51 remain rejected under 35 U.S.C. 103 as being unpatentable over NCT03233347 (Record Version 4/30/2018), NCT02505269 (Record History: 6/8/2018), Ansell et al (2017) (Nivolumab in the Treatment of Hogkin Lymphoma, Clin Cancer Res (2017) 23 (7): 1623–1626), Herrera et al (2018) (Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma, Blood (2018) 131 (11): 1183–1194); and Wang et al (US10562977 B2; Published 1/5/2017) (combined references) as applied to claims 1, 4, 6-9, 13-14, 19, 20, 23, 46-48, 54, and 55 above, and further in view of Kim et al. (Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project. J Clin Oncol. 2015;33(32):3750-3758) and Lesokhin et al. (Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. J Clin Oncol. 2016;34(23):2698-2704)
The teachings of the combined references are cited above, however, they do not teach the hematologic cancer is a CD30 expressing cancer (>30%), such as CD30-positive mycosis fungoides (MF).
Kim teaches a method of treating a hematologic cancer, Mycosis Fungoides (MF) comprising administering an anti-CD30 antibody drug conjugate, Brentuximab vedotin. Kim teaches that MF is a common subtype cutaneous T-cell lymphoma. Kim teaches that brentuximab vedotin has demonstrated dramatic efficacy in the treatment of Hodgkin lymphoma, which both express CD30. [pg 3750, Introduction] Kim teaches that patients with higher CD30 levels responded higher >10%) than patients who had lower CD30 levels <5%. [pg 3752, Biomarkers of Clinical Response] Kim teaches that brentuximab is a promising agent in patients with MF, either administered as monotherapy or in combination with another agent. [pg 3757]
Lesokhin teaches the treatment of a hematologic cancer, MF, comprising administering nivolumab, and teaches nivolumab exhibits antitumor efficacy against MF and have favorable safety profile. [Conclusion]
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to treat a CD30-expressing hematologic cancer, such as CD30-positive mycosis fungoides (MF). One would have been motivated to, and have a reasonable expectation of success, because: (1) the combined references teach treatment of a hematologic cancer comprising administering the instantly claimed combination, (2) Kim teaches a method of treating MF comprising administering Brentuximab vedotin, (3) Lesokhin teaches a method of treating MF comprising administering nivolumab, and (4) Kim teaches that patients with higher levels of CD30 demonstrate better results when treated with brentuximab. Given the recognized need to treat hematologic cancers that express CD30 and MF, and given the known success for treating these cancers comprising administering the agents noted above, one of skill in the art could have pursued treating CD30 expressing hematologic cancer, such as CD30+ mycosis fungoides, with a reasonable expectation of success.
Response to Arguments
Applicants argue as stated above, the claims are not obvious over the combination of NCT03233347, NCT02505269, Ansell, Herrara and Wang, and the disclosure in Kim and Lesokhin do not remedy the deficiencies of the other cited art. Neither Kim nor Lesokhin disclose or suggest a combination treatment using brentuximab vedotin and a chemotherapeutic regimen to treat hematologic cancers. Applicants argue that nothing in the combination of cited art would have motivated one of skill to arrive at the present combination treatment, or had a reasonable expectation of success that the treatment would provide such benefits as described in Lee et al (supra) for the reasons set out in Section IV above.
Applicants’ arguments have been fully considered but they are not persuasive. As noted above, Applicants are arguing individual references and not considering all the references a whole. Examiner points to above arguments.
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