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
Status of the Claims
1. Claims 1-65 are the original claims filed 3/8/2023. IN the Preliminary Amendment of 10/2/2023, claims 1-3, 12, 15, 17, 20, 23, 26, 29, 33-38, 45-50, and 64-65 are amended, claims 4-11, 13-14, 16, 18- 19, 21-22, 24-25, 27-28, 30-32, 39-44 and 51-63 are canceled, and new claims 66-67 are added. Claims 1-3, 12, 15, 17, 20, 23, 26, 29, 33-38, 45-50, and 64-67 are pending.
Priority
2. USAN 18/025 203, filed 03/08/2023, is a National Stage entry of PCT/EP2021/075016, International Filing Date: 09/10/2021, PCT/EP2021/ 075016 Claims Priority from Provisional Application 63/076,797, filed 09/10/2020. The contents of the provisional application are similar to that of the instant application. The contents are hypothetical in both cases for the method dose regimen for treating DLBCL. Written description support and enablement for the claimed invention is provided in ClinicalTrials.gov ID NCT05578976 (GenMab; PTO 892).
Information Disclosure Statement
3. As of 12/29/2025, a total of six (6) IDS are filed: 9/14/2023; 9/14/2023; 9/14/2023; 9/14/2023; 9/14/2023; and 9/14/2023. The corresponding 1449 form is considered and of record. The submissions are in compliance with the provisions of 37 CFR 1.97.
Objections
Drawings
4. The drawing sheet for Figure 1 is objected to because of the use of the term “DuoBody”, which is a trade name or a mark used in commerce. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
5. The abstract of the disclosure is objected to because of indefinite language by use of parenthetical text and the term “e.g.,” The POSA cannot reasonably ascertain whether the subject matter is exemplary or intended description of the invention. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
6. The disclosure is objected to because of the following informalities:
a) The use of the term DuoBody, GenBank, UniProt, Swiss-prot, Crossmab, Expi293, PER.C6, ALIGN, nanobody, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
b) The figure legend to Figure 2 is objected to for failing to identify the meaning of the abbreviations used in the figure, specifically “R-CHOP” and “EPCO.”
Appropriate correction is required.
Claim Objections
7. Claims 1-3, 12, 15, 17, 20, 23, 26, 29, 33-38, 45-50, and 64-67 are objected to because of the following informalities:
a) Claims 1-3, 12, 15, 17, 20, 23, 26, 29, 33-38, 45-50, and 64-67 are unclear for the relation between “a 21-day cycle” (Claim 1(a)(i)-(iii) and (f)) and “once every three weeks” (Claim 1(a)(iii), (b)-(e)). A twenty-one-day cycle necessarily comprises three weeks. It is not clear what if any distinction there is between the claimed limitations.
b) Amend claims 1-3, 12, 15, 17, 20, 23, 26, 29, 33-38, 45-50, and 64-67 for consistency to recite “21-day” or “28-day”.
c) Amend claim 1 to correct a typographical error: “(e) vincristine is administered intravenously 2 once every three weeks;”
d) Amend claim 1 to correct improper punctuation: “(a) epcoritamab or a biosimilar thereof, (b) rituximab,”.
e) Amend claim 1 to correct improper punctuation: “wherein administration of the combination continues at least until the subject exhibits a complete metabolic response (CMR), a partial metabolic response, [or] a stable disease, [or] until progressive disease develops, or unacceptable toxicity occurs.”
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.
8. Claims 1-3, 12, 15, 17, 20, 23, 26, 29, 33-38, 45-50, and 64-67 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.
Claim 1(a)(iv) recites the limitation "28-day cycles". Claims 35, 38 and 66-67 recite “28-day cycles.” There is insufficient antecedent basis for this limitation in the claims. Otherwise, 21-day cycles are specified in Claim 1 reciting “a combination of (a) epcoritamab or a biosimilar thereof (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, (e) vincristine and (f) prednisone, in 21-day cycles” and in elements (a)(i)-(iii) (b)-(f) that recite “21-day cycles”.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
9. Claims 34, 36-37, 45-46 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
a) Claims 34(ii) and (iii), 36(ii) and (iii), and 37 (ii) and (iii) are broadening for reciting “a dose of 48 mg” (Claims 34 and 37) and “a dose of 24 mg” (claim 36) without specifying that the dose is “full” as per claim 1. In depending from claim 1, Claims 34 and 36-37 are broadening in scope.
b) Claims 45-46 recite “the bispecific antibody” whilst claim 1 is amended to replace “a bispecific antibody” with “epicortimab.” IN depending from claim 1, both claims 45-46 are broadening in scope.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Written Description
10. Claims 1-3, 12, 15, 17, 20, 23, 26, 29, 33-38, 45-50, and 64-67 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.
Claim interpretation
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through establishment of a structure-function correlation (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) or through a sufficient description of a representative number of species. Either is considered sufficient to show the applicant was in possession of the claimed genus.
A) Claims 1-3, 12, 15, 17, 20, 23, 26, 29, 33-38, 45-50, and 64-67 are examined for treating DLBCL using the dosage regimen with respect to epcoritamab (EPCO) in a method of treating DLBCL in combination with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP).
Claimed method invention for treating DLBCL using the EPCO/ R-CHOP combination in a dose regimen cycle is examined for its enablement for both therapeutic and prophylactic effects on DLBCL in the human subject.
“therapeutically effective amount”: the specification is unequivocal that treatment encompasses both therapy and prophylaxis.
[0106] The term “effective amount” or “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result…A therapeutically effective amount or dosage of a drug includes a “prophylactically effective amount” or a “prophylactically effective dosage”, which is any amount of the drug that, when administered alone or in combination with another therapeutic agent to a subject at risk of developing a disease or disorder (e.g., cytokine release syndrome) or of suffering a recurrence of disease, inhibits the development or recurrence of the disease.
The specification makes clear that adverse events/ side effects of the drug combination may be medicated to prevent those occurrences (e.g., CRS [0229]; TLS [0240]; other side effects [0241]). But those adverse events/ side effects are to be distinguished from the analysis of the actual prophylactic effect of EPCO/ R-CHOP on DLBCL.
Disclosure in the specification
Those data in Figure 1 (Example 2) for the DuoBody® anti-CD3 x anti-CD20 (EPCO) are not representative of the instant claimed method steps comprising a cyclic dosing pattern for the EPCO/R-CHOP combination. Those data test individually elements (a) and (c), (a) and (d), (a) and (e), and (a) and (f) under, in vitro, conditions for a common target cell to measure viability of CD20-expressing Daudi cells. Those steps in Figures 2 and 3 are hypothetical regimens.
ClinicalTrials.gov ID NCT05578976 (GenMab; PTO 892) teaches “The purpose of this study is to assess the change in disease activity of epcoritamab when combined with intravenous and oral rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP) or R-CHOP in adult participants globally with diffuse large b-cell lymphoma (DLBCL).” NCT ‘976 does not teach or suggest the assessment of prevention for the combination.
No examples are shown for the prevention DLBCL in a human subject using the EPCO/R-CHOP dosage regimen as instant claimed.
B) Claims 1-3, 12, 15, 17, 20, 23, 26, 29, 33-38, 45-50, and 64-67 are examined for the meaning of “biosimilars thereof” with respect to epcoritamab (EPCO) much less those used in a method of treating DLBCL alone or in combination with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). The biosimilars for epcoritamab (EPCO) are examined for possession of functionalized attributes.
“biosimilar”: the specification has a precise definition for a product to qualify as a biosimilar.
[0094] The term “biosimilar” (e.g., of an approved reference product/biological drug) as used herein refers to a biologic product that is similar to the reference product based on data from (a) analytical studies demonstrating that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; (b) animal studies (including the assessment of toxicity); and/or (c) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is approved and intended to be used and for which approval is sought (e.g., that there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product). In some embodiments, the biosimilar biological product and reference product utilizes the same mechanism or mechanisms of action for the condition or conditions of use prescribed, recommended, or suggested in the proposed labeling, but only to the extent the mechanism or mechanisms of action are known for the reference product. In some embodiments, the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product have been previously approved for the reference product. In some embodiments, the route of administration, the dosage form, and/or the strength of the biological product are the same as those of the reference product. A biosimilar can be, e.g., a presently known antibody having the same primary amino acid sequence as a marketed antibody, but may be made in different cell types or by different production, purification, or formulation methods.
Claim 64 is specifically claimed as being a biosimilar of EPCO defined by sequences (SEQ ID NO: 24/25 (FEAL) and 26/27 (FEAR); claim 64). The specification does not define whether FEAL and FEAR meet the criteria under [0094].
Whilst the claims recite “a biosimilar thereof” as regards to the EPCO antibody, the specification is not a source or a guide for the manufacture and testing of EPCO biosimilars that meet the conditions for (a)-(c) set forth under [0094]. Still further, the EPCO biosimilars would need to be functionalized equivalents of EPCO that are effective in treating DLBCL in a human subject in the same combination with R-CHOP. Applicants seek over potentially millions of biosimilars to EPCO much less the EPCO biosimilar/R-CHOP combination in the treatment of DLBCL in a human subject. The breadth and scope of the combination is incalculable much less for the fact that no testing the use of the biosimilars in a dose regimen strategy is demonstrated in the specification and prior art showing both therapeutic and prophylactic effects as a predictable or actual endpoint in the therapy.
Enablement
11. Claims 1-3, 12, 15, 17, 20, 23, 26, 29, 33-38, 45-50, and 64-67 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Factors to be considered in determining whether undue experimentation is required, are summarized in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). They include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability of the art, the breadth of the claims, the quantity of experimentation which would be required in order to practice the invention as claimed.
Claim interpretation
Claimed method invention for treating DLBCL using the EPCO/ R-CHOP combination in a dose regimen cycle is examined for its enablement for prevention or prophylaxis of DLBCL in the human subject.
“therapeutically effective amount”: the specification is unequivocal that treatment encompasses both therapy and prophylaxis.
[0106] The term “effective amount” or “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result…A therapeutically effective amount or dosage of a drug includes a “prophylactically effective amount” or a “prophylactically effective dosage”, which is any amount of the drug that, when administered alone or in combination with another therapeutic agent to a subject at risk of developing a disease or disorder (e.g., cytokine release syndrome) or of suffering a recurrence of disease, inhibits the development or recurrence of the disease.
The specification makes clear that adverse events/ side effects of the drug combination may be medicated to prevent those occurrences (e.g., CRS [0229]; TLS [0240]; other side effects [0241]). But those adverse events/ side effects are to be distinguished from the analysis of the actual prophylactic effect of EPCO/ R-CHOP on DLBCL.
Disclosure in the specification
Those data in Figure 1 (Example 2) for the DuoBody® anti-CD3 x anti-CD20 (EPCO) are not representative of the instant claimed method steps comprising a cyclic dosing pattern for the EPCO/R-CHOP combination. Those data test individually elements (a) and (c), (a) and (d), (a) and (e), and (a) and (f) under, in vitro, conditions for a common target cell to measure viability of CD20-expressing Daudi cells. Those steps in Figures 2 and 3 are hypothetical regimens.
ClinicalTrials.gov ID NCT05578976 (GenMab; PTO 892) teaches “The purpose of this study is to assess the change in disease activity of epcoritamab when combined with intravenous and oral rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP) or R-CHOP in adult participants globally with diffuse large b-cell lymphoma (DLBCL).” NCT ‘976 does not teach or suggest the assessment of prevention for the combination.
No examples are shown for the prevention DLBCL in a human subject using the EPCO/R-CHOP dosage regimen as instant claimed.
Applicants seek over potentially millions of biosimilars to EPCO much less the EPCO biosimilar/R-CHOP combination in the prevention of DLBCL in a human subject. The scope of the combination is incalculable much less for the fact that no preventative strategy is demonstrated in the specification showing prevention as a predictable or actual endpoint in the therapy.
The Patent Act requires that patent applicant describes the invention in explicit terms to enable any person skilled in the art to make and use the invention. 35 U.S.C. 112. The enablement requirement is a crucial aspect of the patent “bargain”: an inventor is granted limited protection from competition in exchange for publicly disclosing their new technology. See the decision in Morse, Incandescent Lamp, and Holland Furniture, establishing the requirement that if a patent claims an entire class or genus of processes, machines, or compositions of matter, the specification must enable a person skilled in the field to make and use the entire class. If a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class. In other words, the specification must enable the full scope of the invention as defined by its claims. The more one claims, the more one must enable. See §112(a); see also Continental Paper Bag Co. v. Eastern Paper Bag Co., 210 U. S. 405 (1908) (“[T]he claims measure the invention.”)
The scope of the claims must bear a reasonable correlation with the scope of enablement. See In re Fisher, 166 USPQ 19, 24 (CCPA 1970). "[T]o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.'" Genentech, Inc. v. Novo Nordisk, A/S, 108 F.3d 1361, 1365 (Fed. Cir. 1997) (quoting In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993)).
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.
12. Claim(s) 1 and 65 is/are rejected under 35 U.S.C. 103 as being unpatentable over Van Den Brink et al. (US 20160333095) in view of Valbjoern (US 20220411505; 8/19/2020) and Mounier et al. (Blood, 2003, 101: 4279-4284, IDS 9/14/2023) as evidenced by Sureda (EMJ Oncol. 2021; 9 [Suppl 8]:2-12 with reference to PeerVoice (20th May 2021)).
The claims are prima facie obvious over Van Den Brink, Valbjoern in view of Mounier and as evidenced by Sureda.
Claims 1 and 65 are drawn to a method of treating diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject a combination of (a) epcoritamab (EPCO) or a biosimilar thereof, (b) rituximab, (c) cyclophosphamide, (d) doxorubicin, (e) vincristine and (f) prednisone (R-CHOP), in 21-day cycles, wherein
(a) epcoritamab or a biosimilar thereof is administered subcutaneously, wherein (i) a priming dose is administered on day 1 of the first 21-day cycle, an intermediate dose is administered on day 8 of the first 21-day cycle, and a full dose of 24 or 48 mg on day 15 of the first 21-day cycle, wherein the priming dose and intermediate dose are at a lower dose as compared with the full dose,
(ii) a full dose of 24 or 48 mg on days 1, 8 and 15 of the second, third and fourth 21- day cycles;
(iii) a full dose of 24 or 48 mg is administered once every three weeks on day 1 of two to four subsequent 21-day cycles; and
(iv) a full dose of 24 or 48 mg is subsequently administered one every four weeks on day 1 in 28-day cycles;
(b) rituximab is administered intravenously at a dose of 375 mg/m2 once every three weeks;
(c) cyclophosphamide is administered intravenously at a dose of 750 mg/m2 once every three weeks;
(d) doxorubicin is administered intravenously at a dose of 50 mg/m2 once every three weeks;
(e) vincristine is administered intravenously weeks at a dose of 1.4 mg/m2 once every three; and
(f) prednisone is administered orally or intravenously at a dose of 100 mg once a day from day 1 to day 5 of each 21-day cycle;
wherein administration of the combination continues at least until the subject exhibits a complete metabolic response (CMR), a partial metabolic response or stable disease, or until progressive disease develops or unacceptable toxicity occurs.
Claim 65 is drawn to administering epcoritamab.
As regards claims 1 and 65, Van Den Brink teaches a method of treatment for aggressive (fast growing like DLBCL) B-cell lymphoma (see [0549]) in a human subject (see [0546]) comprising administering a bispecific antibody to the subject, wherein the bispecific antibody comprises a first binding region which binds to human CD3 epsilon comprises SEQ ID NO: 6 (VH) and SEQ ID NO: 10 (VL), and a second binding region which binds to human CD20 comprises SEQ ID NO: 29 (VH) and SEQ ID NO: 30 (VL); see entire document, e.g. claims 1-7, 40, 45-50 and 59-60, [0481-0496], Example 17.
SEQ ID NOs: 6, 10 and 29-30, respectively, of Van Den Brink et al. are 100% identical with the anti-hCD3E VH/VL 6/7 and anti-hCD20 VH/VL 13/14 domains of instant claimed of epcoritamab (EPCO):
Ref SEQ ID NO: 6 and 10 vs SEQ ID NO: 6 and 7:
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420
554
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278
744
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628
720
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Ref SEQ ID NO: 29 and 30 vs SEQ ID NO: 13 and 14:
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254
564
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448
730
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622
730
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Van Den Brink teaches anti-B-cell lymphoma methods to include rituximab [0483].
Van Den Brink teaches dosages and treatment schedules of the epcoritamab antibody such as
[0553] An exemplary, non-limiting range for a therapeutically effective amount of a humanized or chimeric antibody of the invention is about 0.001-30 mg/kg, such as about 0.001-20 mg/kg, such as about 0.001-10 mg/kg, such as about 0.001-5 mg/kg, for example about 0.001-2 mg/kg, such as about 0.001-1 mg/kg, for instance about 0.001, about 0.01, about 0.1, about 1, about 5, about 8, about 10, about 12, about 15, about 18 mg/kg. See claim 1(a)(ii) for a 24 mg or 48 mg dose.
[0554] Administration may e.g. be intravenous, intramuscular, intraperitoneal, or subcutaneous, and for instance administered proximal to the site of the target. See claim 1(a).
[0555] Dosage regimens in the above methods of treatment and uses are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
[0556] In one embodiment, the efficacy of the treatment is monitored during the therapy, e.g. at predefined points in time.
[0557] If desired, an effective daily dose of a pharmaceutical composition may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In another embodiment, the humanized or chimeric antibody, or pharmaceutical composition is administered by slow continuous infusion over a long period, such as more than 24 hours, in order to minimize any unwanted side effects.
[0558] While it is possible for a humanized or chimeric antibody of the present invention to be administered alone, it is preferable to administer the humanized or chimeric antibody as a pharmaceutical composition as described above.
[0559] An effective dose of a humanized or chimeric antibody of the invention may also be administered using a weekly, biweekly or triweekly dosing period. The dosing period may be restricted to, e.g., 8 weeks, 12 weeks or until clinical progression has been established. Alternatively, an effective dose of a humanized or chimeric antibody of the invention may be administered every second, third or fourth week.
See claim 1(a)(ii) and (iii) and stable disease, where triweekly dosing period is construed as a “21-day cycle” or “every three weeks” in claim 1.
[0560] In one embodiment, the humanized or chimeric antibody may be administered by infusion in a weekly dosage of calculated by mg/m.sup.2. Such dosages can, for example, be based on the mg/kg dosages provided above according to the following: dose (mg/kg) × 70: 1.8. Such administration may be repeated, e.g., 1 to 8 times, such as 3 to 5 times. The administration may be performed by continuous infusion over a period of from 2 to 24 hours, such as of from 2 to 12 hours. In one embodiment, the humanized or chimeric antibody may be administered by slow continuous infusion over a long period, such as more than 24 hours, in order to reduce toxic side effects.
[0561] In one embodiment, the humanized or chimeric antibody may be administered in a weekly dosage of calculated as a fixed dose for up to 8 times, such as from 4 to 6 times when given once a week. Such regimen may be repeated one or more times as necessary, for example, after 6 months or 12 months. Such fixed dosages can, for example, be based on the mg/kg dosages provided above, with a body weight estimate of 70 kg. The dosage may be determined or adjusted by measuring the amount of humanized or chimeric antibody of the present invention in the blood upon administration by for instance taking out a biological sample and using anti-idiotypic antibodies which target the binding region of the humanized or chimeric antibodies of the present invention.
[0562] In one embodiment, the humanized or chimeric antibody may be administered by maintenance therapy, such as, e.g., once a week for a period of 6 months or more.
Under MPEP 2144.05 In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960) (MPEP 716.02(d)).
Valbjoern teaches epcoritamab or biosimilars thereof (see entire specification; claim 17). See instant claim 1(a).
Valbjoern teaches a priming (Day 1) and intermediate (Day 8) dosing (Days of Dosing) in Example 5. Female cynomolgus monkeys received DuoBody-CD3×CD20 in formulations of the invention (30 mM acetate, 150 mM sorbitol, pH 5.5) either via 4 weekly IV infusions (0.01, 0.1 or 1 mg/kg), an IV priming dose (0.01 mg/kg) followed by a IV target dose of 1 mg/kg, or a single SC injection (0.01, 0.1, 1, 10 or 20 mg/kg), as per this overview:
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See instant claim 1(a)(i).
As regards claim 1(b), (c), (d) (e) and (f), Mounier teaches a method of treating diffuse large B-cell lymphoma (DLBCL) comprising administering to a patient in need thereof the R-CHOP chemotherapy regimen comprising rituximab, cyclophosphamide, doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), and prednisone; see entire document, e.g. abstract.
Mounier teaches that patients treated with R-CHOP received the combination of 375 mg/m2 rituximab, 750 mg cyclophosphamide/m2 body surface area on day 1, 50 mg doxorubicin/m2 on day 1, 1.4 mg vincristine/m2, up to a maximal dose of 2 mg, on day 1, and 40 mg prednisone/m2/d for 5 days; see left col. of page 4280. They [patients] had 8 cycles of CHOP, one every 3 weeks. Patients treated with R-CHOP were also given 375 mg/m2 rituximab, on day 1 of each CHOP cycle. See claim 1(b),(c),(d),(e) and (f) for the R-CHOP regimen in a 21-day (or three week) cycle.
Mournier teaches “Tumor responses were assessed after the 8 cycles or at the end of treatment and were classified as complete response (CR), unconfirmed complete response (CRu), partial response, stable disease, or progressive disease”. See as recited in instant claim 1.
As evidenced by Sureda teaches and provides the motivation to consider the combination of epcoritamab with R-CHOP stating the need to identify new strategies using other antibody targets with R-CHOP:
“efforts to improve longterm outcomes in these patients have led to strategies that alter R-CHOP, such as adding a new targeted agent (e.g., bortezomib, ibrutinib, or lenalidomide), replacing a component (e.g., with bortezomib or obinutuzumab), or consolidating remission with maintenance therapy (e.g., rituximab, lenalidomide, enzastaurin, or everolimus).6–14 Unfortunately these efforts have been largely unsuccessful in improving survival in R/R DLBCL.” Col. 1, p.3.
As evidenced by Sureda the motivation to consider the combination of epcoritamab (Table 1) with R-CHOP is such
“As an example, epcoritamab has demonstrated an ORR of 66.7–100.0% of patients with R/R DLBCL, depending on dose percent, with a CR rate of approximately 30%, a substantial improvement over conventional treatments.”
13. Claim(s) 2-3, 12, and 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Van Den Brink et al. (US 20160333095) in view of Valbjoern (US 20220411505; 8/19/2020) and Mounier et al. (Blood, 2003, 101: 4279-4284, IDS 9/14/2023) as evidenced by Sureda (EMJ Oncol. 2021; 9 [Suppl 8]:2-12 with reference to PeerVoice (20th May 2021)) as applied to claim 1 above.
AS regards claims 2-3 (full doses), 12 (priming dose) and 15 (intermediate dose), Van Den Brink teaches dosages and treatment schedules of the epcoritamab antibody such as [0553] An exemplary, non-limiting range for a therapeutically effective amount of a humanized or chimeric antibody of the invention is about 0.001-30 mg/kg, such as about 0.001-20 mg/kg, such as about 0.001-10 mg/kg, such as about 0.001-5 mg/kg, for example about 0.001-2 mg/kg, such as about 0.001-1 mg/kg, for instance about 0.001, about 0.01, about 0.1, about 1, about 5, about 8, about 10, about 12, about 15, about 18 mg/kg.
Here the range of full dosing for EPCO is overlapping with the range “about 0.001-30 mg/kg.”
Valbjoern teaches a priming (Day 1) and intermediate (Day 8) dosing (Days of Dosing) in Example 5. Female cynomolgus monkeys received DuoBody-CD3×CD20 in formulations of the invention (30 mM acetate, 150 mM sorbitol, pH 5.5) either via 4 weekly IV infusions (0.01, 0.1 or 1 mg/kg), an IV priming dose (0.01 mg/kg) followed by a IV target dose of 1 mg/kg, or a single SC injection (0.01, 0.1, 1, 10 or 20 mg/kg), as per this overview:
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Here the range of priming and intermediate dosing for EPCO is overlapping with the range shown in Valbjoern.
14. Claim(s) 17, 20, 23, 26 and 29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Van Den Brink et al. (US 20160333095) in view of Valbjoern (US 20220411505; 8/19/2020) and Mounier et al. (Blood, 2003, 101: 4279-4284, IDS 9/14/2023) as evidenced by Sureda (EMJ Oncol. 2021; 9 [Suppl 8]:2-12 with reference to PeerVoice (20th May 2021)) as applied to claim 1 above.
As regards claims 17 (rituximab timing), 20 (cyclophosphamide timing), 23 doxorubicin timing), 26 (vincristine timing) and 29 (prednisone timing), Mounier teaches patients between 60 and 80 years of age were randomized to receive 8 cycles of either CHOP or R-CHOP every 3 weeks.
15. Claim(s) 33-34 and 36-37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Van Den Brink et al. (US 20160333095) in view of Valbjoern (US 20220411505; 8/19/2020) and Mounier et al. (Blood, 2003, 101: 4279-4284, IDS 9/14/2023) as evidenced by Sureda (EMJ Oncol. 2021; 9 [Suppl 8]:2-12 with reference to PeerVoice (20th May 2021)) as applied to claim 1 above.
AS regards claims 33-34 and 36-37 for the cycling in the administration of alternately 24 mg or 48 mg of EPCO as between claims 33 and 34, and 36 and 37, respectively.
Van Den Brink teaches dosages and treatment schedules of the epcoritamab antibody such as
[0553] An exemplary, non-limiting range for a therapeutically effective amount of a humanized or chimeric antibody of the invention is about 0.001-30 mg/kg, such as about 0.001-20 mg/kg, such as about 0.001-10 mg/kg, such as about 0.001-5 mg/kg, for example about 0.001-2 mg/kg, such as about 0.001-1 mg/kg, for instance about 0.001, about 0.01, about 0.1, about 1, about 5, about 8, about 10, about 12, about 15, about 18 mg/kg.
[0554] Administration may e.g. be intravenous, intramuscular, intraperitoneal, or subcutaneous, and for instance administered proximal to the site of the target.
[0555] Dosage regimens in the above methods of treatment and uses are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
[0556] In one embodiment, the efficacy of the treatment is monitored during the therapy, e.g. at predefined points in time.
[0557] If desired, an effective daily dose of a pharmaceutical composition may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In another embodiment, the humanized or chimeric antibody, or pharmaceutical composition is administered by slow continuous infusion over a long period, such as more than 24 hours, in order to minimize any unwanted side effects.
[0558] While it is possible for a humanized or chimeric antibody of the present invention to be administered alone, it is preferable to administer the humanized or chimeric antibody as a pharmaceutical composition as described above.
[0559] An effective dose of a humanized or chimeric antibody of the invention may also be administered using a weekly, biweekly or triweekly dosing period. The dosing period may be restricted to, e.g., 8 weeks, 12 weeks or until clinical progression has been established. Alternatively, an effective dose of a humanized or chimeric antibody of the invention may be administered every second, third or fourth week.
[0560] In one embodiment, the humanized or chimeric antibody may be administered by infusion in a weekly dosage of calculated by mg/m.sup.2. Such dosages can, for example, be based on the mg/kg dosages provided above according to the following: dose (mg/kg) × 70: 1.8. Such administration may be repeated, e.g., 1 to 8 times, such as 3 to 5 times. The administration may be performed by continuous infusion over a period of from 2 to 24 hours, such as of from 2 to 12 hours. In one embodiment, the humanized or chimeric antibody may be administered by slow continuous infusion over a long period, such as more than 24 hours, in order to reduce toxic side effects.
[0561] In one embodiment, the humanized or chimeric antibody may be administered in a weekly dosage of calculated as a fixed dose for up to 8 times, such as from 4 to 6 times when given once a week. Such regimen may be repeated one or more times as necessary, for example, after 6 months or 12 months. Such fixed dosages can, for example, be based on the mg/kg dosages provided above, with a body weight estimate of 70 kg. The dosage may be determined or adjusted by measuring the amount of humanized or chimeric antibody of the present invention in the blood upon administration by for instance taking out a biological sample and using anti-idiotypic antibodies which target the binding region of the humanized or chimeric antibodies of the present invention.
[0562] In one embodiment, the humanized or chimeric antibody may be administered by maintenance therapy, such as, e.g., once a week for a period of 6 months or more.
Valbjoern teaches a priming (Day 1) and intermediate (Day 8) dosing (Days of Dosing) in Example 5. Female cynomolgus monkeys received DuoBody-CD3×CD20 in formulations of the invention (30 mM acetate, 150 mM sorbitol, pH 5.5) either via 4 weekly IV infusions (0.01, 0.1 or 1 mg/kg), an IV priming dose (0.01 mg/kg) followed by a IV target dose of 1 mg/kg, or a single SC injection (0.01, 0.1, 1, 10 or 20 mg/kg), as per this overview:
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Here the range of priming and intermediate dosing for EPCO is overlapping with the range shown in Valbjoern.
Mounier teaches patients between 60 and 80 years of age were randomized to receive 8 cycles of either CHOP or R-CHOP every 3 weeks.
Under MPEP 2144.05 In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960) (MPEP 716.02(d)).
16. Claim(s) 45-46 is/are rejected under 35 U.S.C. 103 as being unpatentable over Van Den Brink et al. (US 20160333095) in view of Valbjoern (US 20220411505; 8/19/2020) and Mounier et al. (Blood, 2003, 101: 4279-4284, IDS 9/14/2023) as evidenced by Sureda (EMJ Oncol. 2021; 9 [Suppl 8]:2-12 with reference to PeerVoice (20th May 2021)) as applied to claim 1 above.
As regards claims 45-46 (order of administration of EPCO and R-CHOP) is obvious to try as evidenced by Sureda that teaches and provides the motivation to consider the combination of epcoritamab with R-CHOP stating the need to identify new strategies using other antibody targets with R-CHOP:
“efforts to improve longterm outcomes in these patients have led to strategies that alter R-CHOP, such as adding a new targeted agent (e.g., bortezomib, ibrutinib, or lenalidomide), replacing a component (e.g., with bortezomib or obinutuzumab), or consolidating remission with maintenance therapy (e.g., rituximab, lenalidomide, enzastaurin, or everolimus).6–14 Unfortunately these efforts have been largely unsuccessful in improving survival in R/R DLBCL.” Col. 1, p.3.
As evidenced by Sureda the motivation to consider the combination of epcoritamab (Table 1) with R-CHOP is such
“As an example, epcoritamab has demonstrated an ORR of 66.7–100.0% of patients with R/R DLBCL, depending on dose percent, with a CR rate of approximately 30%, a substantial improvement over conventional treatments.”
17. Claim(s) 47-50 is/are rejected under 35 U.S.C. 103 as being unpatentable over Van Den Brink et al. (US 20160333095) in view of Valbjoern (US 20220411505; 8/19/2020) and Mounier et al. (Blood, 2003, 101: 4279-4284, IDS 9/14/2023) as evidenced by Sureda (EMJ Oncol. 2021; 9 [Suppl 8]:2-12 with reference to PeerVoice (20th May 2021)) as applied to claim 1 above, and further in view of Kramer (PTO 892).
As regards claim 47 (double- or triple-hit DLBCL), Mounier by way of incorporation to Kramer teaches Overexpression of bcl-2 protein in NHLcells, which is not correlated to chromosome 14;18 translocation, has been incriminated in their resistance to chemotherapy both in vitro and in vivo, where BCL2, BCL6, and MYC rearrangements in diffuse large B-cell lymphoma are what confer double- or triple-hit DLBCL.
AS regards claims 48 (follicular lymphoma), 49 (IPI), and 50 (no prior treatment), Mounier teaches “In all, 399 patients were enrolled in the LNH-98-5 trial; the histologic material from 385 was reviewed: 49 did not have DLBCL, 4 had histologic transformation of a follicular lymphoma, and 332 had confirmed DLBCL.”
Mounier teaches an IPI of 3 in Table 1. Mounier by way of incorporation to teaches “Briefly, patients were eligible if they were 60 to 80 years of age and had untreated DLBCL.”
18. Claim(s) 64 is/are rejected under 35 U.S.C. 103 as being unpatentable over Van Den Brink et al. (US 20160333095) in view of Valbjoern (US 20220411505; 8/19/2020) and Mounier et al. (Blood, 2003, 101: 4279-4284, IDS 9/14/2023) as evidenced by Sureda (EMJ Oncol. 2021; 9 [Suppl 8]:2-12 with reference to PeerVoice (20th May 2021)) as applied to claim 1 above.
As regards claim 64, SEQ ID NOs: 6, 10 and 29-30, respectively, of Van Den Brink are 100% identical with the anti-hCD3E VH/VL 6/7 and anti-hCD20 VH/VL 13/14 domains of instant claimed of epcoritamab (EPCO). Instant claimed SEQ ID NO: 24/25 are 100% identical with SEQ ID NO: 6/7 of EPCO:
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Instant claimed SEQ ID NO: 26/27 are 100% identical with SEQ ID NO: 13/14 of EPCO:
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By transitive reasoning, the sequences of claim 64 are identical to the sequences of Van Den Brink that teaches EPCO.
19. Claim(s) 1(iv), 35, 38 and 66-67 is/are rejected under 35 U.S.C. 103 as being unpatentable over Van Den Brink et al. (US 20160333095) in view of Valbjoern (US 20220411505; 8/19/2020) and Mounier et al. (Blood, 2003, 101: 4279-4284, IDS 9/14/2023) as evidenced by Sureda (EMJ Oncol. 2021; 9 [Suppl 8]:2-12 with reference to PeerVoice (20th May 2021)) as applied to claim 1 above.
As regards claims 1(iv), 35, 38 and 66-67 for EPCO being administered in “28-day cycles” (or 4 week cycles), Van Den Brink teaches “Alternatively, an effective dose of a humanized or chimeric antibody of the invention may be administered every second, third or fourth week.”
It would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of the references so as to treat DLBCL patient comprising ani-CD3 and anti-CD20 bispecific antibody (epcoritamab), and the R-CHOP regimen comprising rituximab, cyclophosphamide, doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), and prednisone. One would have been motivated to do so because Van Den Brink and Valbjoern teach a method of treatment of DLBCL cancer in a subject comprising administering an anti-CD3 and anti-CD20 bispecific antibody to the subject; Mounier teaches a method of treating DLBCL comprising administering to a patient in need thereof the R-CHOP regimen. As evidenced by Sureda, RCHOP therapies in combination with other antibody therapies have had mixed results, that epcoritamab in clinical trial status is a putative target therapy to be used in combination with RCHOP.
Thus, by way of the combination of references, one of ordinary skill in the art would have a reasonable expectation of success where the reagents are available for dosing in bioassays and/or animal models for therapeutic regimens in treating DLBCL. It is prima facie obvious to combine two therapeutic agents, each of which is taught by the prior art to be useful for the same purpose, in order to form a combination that is to be used for the very same purpose. The idea of combining the first and second therapeutic agents to form a third flows logically from having the first and second been individually taught in the prior art. See In re Kerkhoven, 205 USPQ 1069 (CCPA 1980); see M.P.E.P. § 2144.06. In this case, both anti-CD3 and anti-CD20 bispecific antibody (EPCO), and the R-CHOP therapy regimen are taught by the prior art for treating DLBCL cancer.
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.
20. Claims 1-3, 12, 15, 17, 20, 23, 26, 29, 33-38, 45-50, and 64-67 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-33 of U.S. Patent No. 11845805 in view of Van Den Brink et al. (US 20160333095) in view of Valbjoern (US 20220411505; 8/19/2020) and Mounier et al. (Blood, 2003, 101: 4279-4284, IDS 9/14/2023) as evidenced by Sureda (EMJ Oncol. 2021; 9 [Suppl 8]:2-12 with reference to PeerVoice (20th May 2021)).
Ref claims
1. A method of treating diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject a bispecific antibody, and an effective amount of (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine and (e) prednisone, wherein the bispecific antibody comprises: (i) a first binding arm comprising a first antigen-binding region which binds to human CD3c (epsilon) and comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the CDR1, CDR2 and CDR3 sequences that are in the VH sequence of SEQ ID NO: 6, and the VL comprises the CDR1, CDR2 and CDR3 sequences that are in the VL sequence of SEQ ID NO: 7; and (ii) a second binding arm comprising a second antigen-binding region which binds to human CD20 and comprises a VH and a VL, wherein the VH comprises the CDR1, CDR2 and CDR3 sequences that are in the VH sequence of SEQ ID NO: 13, and the VL comprises the CDR1, CDR2 and CDR3 sequences that are in the VL sequence of SEQ ID NO: 14; wherein rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, and the bispecific antibody are administered in 21-day cycles; and wherein (a) a priming dose of the bispecific antibody is administered on day 1 of cycle 1 of the 21-day cycles, an intermediate dose of the bispecific antibody is administered on day 8 of cycle 1 of the 21-day cycles, a dose of 24 mg or 48 mg of the bispecific antibody is administered on day 15 of cycle 1 of the 21-day cycles, and a dose of 24 or 48 mg of the bispecific antibody is administered weekly starting on day 1 of cycle 2 of the 21-day cycles; (b) rituximab is administered once every three weeks for six or eight 21-day cycles, and (c) cyclophosphamide is administered once every three weeks for six or eight 21-day cycles, and (d) doxorubicin is administered once every three weeks for six or eight 21-day cycles, and (e) vincristine is administered once every three weeks for six or eight 21-day cycles, and (f) prednisone is administered once a day from day 1 to day 5 of each 21-day cycles for six or eight 21-day cycles.
2. The method of claim 1, wherein the bispecific antibody is administered at a weekly dose of 24 mg starting on day 1 of cycle 2 of the 21-day cycles.
3. The method of claim 1, wherein the bispecific antibody is administered at a weekly dose of 48 mg starting on day 1 of cycle 2 of the 21-day cycles.
4. The method of claim 1, wherein the weekly administration of 24 mg or 48 mg of the bispecific antibody is performed for three and one-third 21-day cycles.
5. The method of claim 4, wherein after the weekly administration of the bispecific antibody for three and one-third 21-day cycles, the bispecific antibody is administered once every three weeks for two or four 21-day cycles.
6. The method of claim 5, wherein after the administration of the bispecific antibody once every three weeks for two or four 21-day cycles, the bispecific antibody is administered once every four weeks in 28-day cycles for up to one year total duration of treatment with the bispecific antibody.
7. The method of claim 1, wherein (a) the priming dose of the bispecific antibody is 0.16 mg, (b) intermediate dose of the bispecific antibody is 0.8 mg, or (c) the priming dose of the bispecific antibody is 0.16 mg and the intermediate dose of the bispecific antibody is 0.8 mg.
8. The method of claim 1, wherein rituximab is administered at a dose of 375 mg/m.sup.2, cyclophosphamide is administered at a dose of 750 mg/m.sup.2, doxorubicin is administered at a dose of 50 mg/m.sup.2, vincristine is administered at a dose of 1.4 mg/m.sup.2, and prednisone is administered at a dose of 100 mg/day.
9. The method of claim 1, wherein: (a) the bispecific antibody is administered as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg or 48 mg is administered on day 15; (ii) in cycles 2-4, a dose of 24 mg or 48 mg is administered on days 1, 8, and 15; (iii) in cycles 5 and 6, a dose of 24 mg or 48 mg is administered on day 1; (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-6; and (c) prednisone is administered on days 1-5 in cycles 1-6.
10. The method of claim 9, wherein the bispecific antibody is administered once every four weeks in 28-day cycles on day 1 from cycle 7.
11. The method of claim 1, wherein: (a) the bispecific antibody is administered as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg or 48 mg is administered on day 15; (ii) in cycles 2-4, a dose of 24 mg or 48 mg is administered on days 1, 8, and 15; (iii) in cycles 5-8, a dose of 24 mg or 48 mg is administered on day 1; (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-8; and (c) prednisone is administered on days 1-5 in cycles 1-8.
12. The method of claim 11, wherein the bispecific antibody is administered once every four weeks in 28-day cycles on day 1 from cycle 9.
13. The method of claim 1, wherein the bispecific antibody is administered subcutaneously.
14. The method of claim 1, wherein rituximab is administered intravenously, wherein cyclophosphamide is administered intravenously, wherein doxorubicin is administered intravenously, wherein vincristine is administered intravenously and wherein prednisone is administered intravenously or orally.
15. The method of claim 1, wherein (a) the DLBCL is double-hit or triple-hit DLBCL, and/or (b) the DLBCL is follicular lymphoma Grade 3B, and/or (c) the subject has an International Prognostic Index (IPI) score or Revised-IPI score>3, and/or (d) the subject has not received prior therapy for DLBCL or follicular lymphoma Grade 3B.
16. The method of claim 1, wherein: (i) the VH and VL of the first antigen-binding region of the bispecific antibody comprise the amino acid sequence of SEQ ID NO: 6 and SEQ ID NO: 7, respectively; and (ii) the VH and VL of the second antigen-binding region of the bispecific antibody comprise the amino acid sequence of SEQ ID NO: 13 and SEQ ID NO: 14, respectively.
17. The method of claim 1, wherein the first binding arm of the bispecific antibody is derived from a humanized antibody and comprises a λ light chain constant region comprising the amino acid sequence set forth in SEQ ID NO: 22 and/or the second binding arm of the bispecific antibody is derived from a human antibody and comprises a κ light chain constant region comprising the amino acid sequence set forth in SEQ ID NO: 23.
18. The method of claim 1, wherein the bispecific antibody is a full-length antibody with a human IgG1 constant region.
19. The method of claim 1, wherein the bispecific antibody comprises an inert Fc region.
20. The method of claim 1, wherein the bispecific antibody comprises a first heavy chain and a second heavy chain, wherein (i) in both the first and second heavy chains, the amino acids in the positions corresponding to positions L234, L235, and D265 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 are F, E, and A, respectively, and (ii) in the first heavy chain, the amino acid in the position corresponding to F405 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 is L, and wherein in the second heavy chain, the amino acid in the position corresponding to K409 in the human IgG1 heavy chain constant region of SEQ ID NO: 15 is R, or vice versa.
21. The method of claim 1, wherein the bispecific antibody comprises heavy chain constant regions comprising the amino acid sequences of SEQ ID NOs: 19 and 20.
22. The method of claim 1, wherein the bispecific antibody comprises a first heavy chain and a first light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a second heavy chain and a second light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively.
23. The method of claim 1, wherein the bispecific antibody is epcoritamab, or a biosimilar thereof.
24. A method of treating diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject a bispecific antibody, and an effective amount of (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine and (e) prednisone, wherein the bispecific antibody comprises a first heavy chain and a first light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a second heavy chain and a second light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively, and wherein rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, and the bispecific antibody are administered in 21-day cycles, wherein: (a) the bispecific antibody is administered as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg or 48 mg is administered on day 15; (ii) in cycles 2-4, a dose of 24 mg or 48 mg is administered on days 1, 8, and 15; (iii) in cycles 5 and 6, a dose of 24 mg or 48 mg is administered on day 1; (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-6; and (c) prednisone is administered on days 1-5 in cycles 1-6.
25. The method of claim 24, wherein the bispecific antibody is administered once every four weeks in 28-day cycles on day 1 from cycle 7.
26. A method of treating diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject a bispecific antibody, and an effective amount of (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine and (e) prednisone, wherein the bispecific antibody comprises a first heavy chain and a first light chain comprising the amino acid sequences set forth in SEQ ID NOs: 24 and 25, respectively, and a second heavy chain and a second light chain comprising the amino acid sequences set forth in SEQ ID NOs: 26 and 27, respectively, and wherein rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, and the bispecific antibody are administered in 21-day cycles, wherein: (a) the bispecific antibody is administered as follows: (i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg or 48 mg is administered on day 15; (ii) in cycles 2-4, a dose of 24 mg or 48 mg is administered on days 1, 8, and 15; (iii) in cycles 5-8, a dose of 24 mg or 48 mg is administered on day 1; (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-8; and (c) prednisone is administered on days 1-5 in cycles 1-8.
27. The method of claim 26, wherein the bispecific antibody is administered once every four weeks in 28-day cycles on day 1 from cycle 9.
28. The method of claim 1, wherein administration of (a) rituximab, (b) cyclophosphamide, (c) doxorubicin, (d) vincristine and (e) prednisone in 21-day cycles continues at least until the subject exhibits a complete metabolic response (CMR), or a partial metabolic response.
29. A method of treating diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject a combination of epcoritamab, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, wherein the combination is administered in 21-day cycles; and wherein (a) a priming dose of epcoritamab is administered subcutaneously on day 1 of cycle 1 of the 21-day cycles, an intermediate dose of epcoritamab is administered subcutaneously on day 8 of cycle 1 of the 21-day cycles, a full dose of 24 mg or 48 mg of epcoritamab is subcutaneously administered on day 15 of cycle 1 of the 21-day cycles, and a full dose of 24 or 48 mg of the epcoritamab is administered subcutaneously weekly starting on day 1 of cycle 2 of the 21-day cycles, wherein the priming dose and intermediate dose are at a lower dose as compared with the full dose; (b) rituximab is administered intravenously at a dose of 375 mg/m.sup.2 once every three weeks for six or eight 21-day cycles; (c) cyclophosphamide is administered intravenously at a dose of 750 mg/m.sup.2 once every three weeks for six or eight 21-day cycles; (d) doxorubicin is administered intravenously at a dose of 50 mg/m.sup.2 once every three weeks for six or eight 21-day cycles; (e) vincristine is administered intravenously at a dose of 1.4 mg/m.sup.2 once every three weeks for six or eight 21-day cycles; and (f) prednisone is administered intravenously or orally at a dose of 100 mg/day once a day from day 1 to day 5 of each 21-day cycles for six or eight 21-day cycles; wherein administration of the combination in 21-day cycles continues at least until the subject exhibits a complete metabolic response (CMR), or a partial metabolic response.
30. The method of claim 29, wherein the epcoritamab is administered at a full dose of 24 mg.
31. The method of claim 29, wherein the epcoritamab is administered at a full dose of 48 mg.
32. The method of claim 29, wherein the priming dose of epcoritamab is 0.16 mg.
33. The method of claim 29, wherein the intermediate dose of epcoritamab is 0.8 mg, in view of Van Den Brink et al. (US 20160333095) in view of Valbjoern (US 20220411505; 8/19/2020) and Mounier et al. (Blood, 2003, 101: 4279-4284, IDS 9/14/2023) as evidenced by Sureda (EMJ Oncol. 2021; 9 [Suppl 8]:2-12 with reference to PeerVoice (20th May 2021)).
The analysis for the reference art set forth above is incorporated.
It would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of the references so as to treat DLBCL patient comprising ani-CD3 and anti-CD20 bispecific antibody (epcoritamab), and the R-CHOP regimen comprising rituximab, cyclophosphamide, doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), and prednisone. One would have been motivated to do so because Van Den Brink and Valbjoern teach a method of treatment of DLBCL cancer in a subject comprising administering an anti-CD3 and anti-CD20 bispecific antibody to the subject; Mounier teaches a method of treating DLBCL comprising administering to a patient in need thereof the R-CHOP regimen. As evidenced by Sureda, RCHOP therapies in combination with other antibody therapies have had mixed results, that epcoritamab in clinical trial status is a putative target therapy to be used in combination with RCHOP.
Thus, by way of the combination of references, one of ordinary skill in the art would have a reasonable expectation of success where the reagents are available for dosing in bioassays and/or animal models for therapeutic regimens in treating DLBCL. It is prima facie obvious to combine two therapeutic agents, each of which is taught by the prior art to be useful for the same purpose, in order to form a combination that is to be used for the very same purpose. The idea of combining the first and second therapeutic agents to form a third flows logically from having the first and second been individually taught in the prior art. See In re Kerkhoven, 205 USPQ 1069 (CCPA 1980); see M.P.E.P. § 2144.06. In this case, both anti-CD3 and anti-CD20 bispecific antibody (EPCO), and the R-CHOP therapy regimen are taught by the prior art for treating DLBCL cancer.
21. Claims 1-3, 12, 15, 17, 20, 23, 26, 29, 33-38, 45-50, and 64-67 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 12, 15, 17, 20, 23, 26, 29, 33-38, 46-50, 64-67 of copending Application No. 18/500,799 (US 20240301078) in view of Van Den Brink et al. (US 20160333095) in view of Valbjoern (US 20220411505; 8/19/2020) and Mounier et al. (Blood, 2003, 101: 4279-4284, IDS 9/14/2023) as evidenced by Sureda (EMJ Oncol. 2021; 9 [Suppl 8]:2-12 with reference to PeerVoice (20th May 2021)).
Ref claims
1. (Currently Amended) A method of treating diffuse large B-cell lymphoma (DLBCL) in a human subject, the method comprising administering to the subject a bispecific antibody, and an effective amount of a combination of (a) epcoritamab or a biosimilar thereof (ab) rituximab, (bc) cyclophosphamide, (ed) doxorubicin, (de) vincristine and (ef) prednisone, in 21-day cycles, wherein (a) epcoritamab or a biosimilar thereof is administered subcutaneously, wherein (i) a priming dose is administered on day 1 of the first 21-day cycle, an intermediate dose is administered on day 8 of the first 21-day cycle, and a full dose of 24 or 48 mg on day 15 of the first 21-day cycle, wherein the priming dose and intermediate dose are at a lower dose as compared with the full dose,(ii) a full dose of 24 or 48 mg on days 1, 8 and 15 of the second, third and fourth 21- day cycles;(iii) a full dose of 24 or 48 mg is administered once every three weeks on day 1 of two to four subsequent 21-day cycles; and(iv) a full dose of 24 or 48 mg is subsequently administered one every four weeks on day 1 in 28-day cycles;(b) rituximab is administered intravenously at a dose of 375 mg/m2 once every three weeks;(c) cyclophosphamide is administered intravenously at a dose of 750 mg/m2 once every three weeks;(d) doxorubicin is administered intravenously at a dose of 50 mgz/m2 once every three weeks;(e) vincristine is administered intravenously weeks at a dose of 1.4 mg/m2 once every three ;and (f) prednisone is administered orally or intravenously at a dose of 100 mg once a day from day 1 to day 5 of each 21 day cycle;wherein administration of the combination continues at least until the subject exhibits a complete metabolic response (CMR), a partial metabolic response or stable disease, or until progressive disease develops or unacceptable toxicity occurswherein the a bispecific antibody comprises:(i) a first binding arm comprising a first antigen-binding region which binds to human CD3c (epsilon) and comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises the CDR1, CDR2 and CDR3 sequences that are in the VH region sequence of SEQ ID NO: 6, and the VL region comprises the CDR1, CDR2 and CDR3 sequences that are in the VL region sequence of SEQ ID NO: 7; and(ii) a second binding arm comprising a second antigen-binding region which binds to human CD20 and comprises a VH region and a VL region, wherein the VH region comprises the CDR1, CDR2 and CDR3 sequences that are in the VH region sequence of SEQ ID NO: 13, and the VL region comprises the CDR1, CDR2 and CDR3 sequences that are in the VL region sequence of SEQ ID NO: 14;wherein the bispecific antibody is administered at a dose of 24 mg or 48 mg, and wherein rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, and the bispecific antibody are administered in 21-day cycles.
2. (Currently Amended) The method of claim 1, wherein epcoritamab or a biosimilar thereof the bispecific antibody is administered at a full dose of 24 mg.
3. (Currently Amended) The method of claim 1, wherein epcoritamab or a biosimilar thereof the bispecific antibody is administered at a full dose of 48 mg.
4-11. (Canceled)
12. (Currently Amended) The method of claim 10 or 11 claim 1,wherein the priming dose is 0.16 mg.
13-14. (Canceled)
15. (Currently Amended) The method of claim 13 or 14claim1,wherein the intermediate dose is 0.8 mg.
16. (Canceled)
17. (Currently Amended) The method of claim 16claim1,wherein the administration of rituximab once every three weeks is performed for six or eight 21-day cycles.
18-19. (Canceled)
20. (Currently Amended) The method of claim 19claim1,wherein the administration of cyclophosphamide once every three weeks is performed for six or eight 21-day cycles.
21-22. (Canceled)
23. (Currently Amended) The method of claim 22claim1,wherein the administration of doxorubicin once every three weeks is performed for six or eight 21-day cycles.
24-25. (Canceled)
26. (Currently Amended) The method of claim 25claim1,wherein the administration of vincristine once every three weeks is performed for six or eight 21-day cycles.
27-28. (Canceled)
29. (Currently Amended) The method of claim 28claim1,wherein prednisone is administered for six or eight 21-day cycles.
30-32. (Canceled)
33. (Currently Amended) The method of any one of claimsclaim 1, 2, and 4-32, wherein administration is performed in 21-day cycles, and wherein:(a) the bispecific antibody epcoritamab or a biosimilar thereof is administered as follows:(i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg is administered on day 15; (ii) in cycles 2-4, a full dose of 24 mg is administered on days 1, 8, and 15; (iii) in cycles 5 and 6, a fulldose of 24 mg is administered on day 1; (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-6; and (c) prednisone is administered on days 1-5 in cycles 1-6.
34. (Currently Amended) The method of any one of claimsclaim 12 and 3-32, wherein administration is performed in 21-day cycles, and wherein:(a) the bispecific antibody epcoritamab or a biosimilar thereof is administered as follows:(i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 48 mg is administered on day 15; (ii) in cycles 2-4, a dose of 48 mg is administered on days 1, 8, and 15; (iii) in cycles 5 and 6, a dose of 48 mg is administered on day 1; (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-6; and (c) prednisone is administered on days 1-5 in cycles 1-6.
35. (Currently Amended) The method of claim 332or 34 wherein the bispecific antibody epcoritamab or a biosimilar thereof is administered once every four weeks in 28-day cycles on day 1 from cycle 7.
36. (Currently Amended) The method of any one of claimsclaim 1, 2, and 4-32, wherein administration is performed in 21-day cycles, and wherein:(a) the bispecific antibody epcoritamab or a biosimilar thereof is administered as follows:(i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 24 mg is administered on day 15; (ii) in cycles 2-4, a dose of 24 mg is administered on days 1, 8, and 15; (iii) in cycles 5-8, a dose of 24 mg is administered on day 1; (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-8; and (c) prednisone is administered on days 1-5 in cycles 1-8.
37. (Currently Amended) The method of any one of claims claim 1 and 3-32, wherein administration is performed in 21-day cycles, and wherein:(a) the bispecific antibody epcoritamab or a biosimilar thereof is administered as follows:(i) in cycle 1, a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a dose of 48 mg is administered on day 15; (ii) in cycles 2-4, a dose of 48 mg is administered on days 1, 8, and 15; (iii) in cycles 5-8, a dose of 48 mg is administered on day 1; (b) rituximab, cyclophosphamide, doxorubicin, and vincristine are administered on day 1 in cycles 1-8; and (c) prednisone is administered on days 1-5 in cycles 1-8.
38. (Currently Amended) The method of claim 36 or 37,wherein the bispecific antibodyepcoritamab or a biosimilar thereof is administered once every four weeks in 28-day cycles on day 1 from cycle 9.
39-44. (Canceled)
45. (Currently Amended) The method of any one of claims 1-44claim1,wherein rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, and the bispecific antibody are administered sequentially.
46. (Currently Amended) The method of any one of claims 1-45claim1,wherein prednisone is administered first, rituximab is administered second, cyclophosphamide is administered third, doxorubicin is administered fourth, vincristine is administered fifth, and the bispecific antibody epcoritamab or a biosimilar thereof is administered last if rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, and the bispecific antibody are administered on the same day.
47. (Currently Amended) The method of any one of claims 1-46claim1,wherein the DLBCL is double-hit or triple-hit DLBCL.
48. (Currently Amended) The method of any one of claims 1-47claim1,wherein the DLBCL is follicular lymphoma Grade 3B.
49. (Currently Amended) The method of any one of claims 1-48claim1,wherein the subject has an International Prognostic Index (IPI) score or Revised-IPI score >3.
50. (Currently Amended) The method of any one of claims 1-49claim1,wherein the subject has not received prior therapy for DLBCL or follicular lymphoma Grade 3B.
51-63. (Canceled)
64. (Currently Amended) The method of any one of claims 1-63claim1,wherein the bispecific antibody comprises method comprises administering a biosimilar of epcoritamab comprising a heavy chain and a light chain consisting of the amino acid sequence of SEQ ID NOs: 24 and 25, respectively, and a heavy chain and a light chain consisting of the amino acid sequence of SEQ ID NOs: 26 and 27, respectively.
65. (Currently Amended) The method of any one of claims 1-64claim1,wherein the bispecific antibody is method comprises administration of epcoritamab, or a biosimilar thereof.
66. (New) The method of claim 34, wherein epcoritamab or a biosimilar thereof is administered once every four weeks in 28-day cycles on day 1 from cycle 7.
67. (New) The method of claim 37, wherein epcoritamab or a biosimilar thereof is administered once every four weeks in 28-day cycles on day 1 from cycle 9,
in view of Van Den Brink et al. (US 20160333095) in view of Valbjoern (US 20220411505; 8/19/2020) and Mounier et al. (Blood, 2003, 101: 4279-4284, IDS 9/14/2023) as evidenced by Sureda (EMJ Oncol. 2021; 9 [Suppl 8]:2-12 with reference to PeerVoice (20th May 2021)).
The analysis for the reference art set forth above is incorporated.
It would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of the references so as to treat DLBCL patient comprising ani-CD3 and anti-CD20 bispecific antibody (epcoritamab), and the R-CHOP regimen comprising rituximab, cyclophosphamide, doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), and prednisone. One would have been motivated to do so because Van Den Brink and Valbjoern teach a method of treatment of DLBCL cancer in a subject comprising administering an anti-CD3 and anti-CD20 bispecific antibody to the subject; Mounier teaches a method of treating DLBCL comprising administering to a patient in need thereof the R-CHOP regimen. As evidenced by Sureda, RCHOP therapies in combination with other antibody therapies have had mixed results, that epcoritamab in clinical trial status is a putative target therapy to be used in combination with RCHOP.
Thus, by way of the combination of references, one of ordinary skill in the art would have a reasonable expectation of success where the reagents are available for dosing in bioassays and/or animal models for therapeutic regimens in treating DLBCL. It is prima facie obvious to combine two therapeutic agents, each of which is taught by the prior art to be useful for the same purpose, in order to form a combination that is to be used for the very same purpose. The idea of combining the first and second therapeutic agents to form a third flows logically from having the first and second been individually taught in the prior art. See In re Kerkhoven, 205 USPQ 1069 (CCPA 1980); see M.P.E.P. § 2144.06. In this case, both anti-CD3 and anti-CD20 bispecific antibody (EPCO), and the R-CHOP therapy regimen are taught by the prior art for treating DLBCL cancer.
This is a provisional nonstatutory double patenting rejection.
22. Claims 1-3, 12, 15, 17, 20, 23, 26, 29, 33-38, 45-50, and 64-67 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of U.S. Patent No. 12435154 in view of Van Den Brink et al. (US 20160333095) in view of Valbjoern (US 20220411505; 8/19/2020) and Mounier et al. (Blood, 2003, 101: 4279-4284, IDS 9/14/2023) as evidenced by Sureda (EMJ Oncol. 2021; 9 [Suppl 8]:2-12 with reference to PeerVoice (20th May 2021)).
Ref claims
1. A method of treating a B-cell non-Hodgkin lymphoma (B-NHL) in a human subject, the method comprising subcutaneously administering a dose of 0.16 mg of epcoritamab to the subject on day one (1) of treatment and subcutaneously administering a dose of 0.8 mg of epcoritamab to the subject on day eight (8) of treatment, wherein the subject does not experience cytokine release syndrome (CRS) or experiences manageable cytokine release syndrome of grade 1 or grade 2, and wherein after day eight (8) of treatment epcoritamab is subcutaneously administered in intervals to the subject until progressive disease develops or unacceptable toxicity occurs.
2. The method of claim 1, wherein 48 mg of epcoritamab is administered subcutaneously to the human subject on days 15 and 22 of treatment.
3. The method of claim 2, wherein said B-NHL is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal-zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL), and wherein the patient achieves a complete response (CR).
4. The method of claim 3, wherein said B-NHL is diffuse large B-cell lymphoma (DLBCL).
5. The method of claim 3, wherein said B-NHL is mantle cell lymphoma (MCL).
6. The method of claim 3, wherein said B-NHL is follicular lymphoma (FL).
7. The method of claim 3, wherein said B-NHL is marginal-zone lymphoma (MZL).
8. The method of claim 3, wherein said B-NHL is small lymphocytic lymphoma (SLL).
9. The method of claim 3, wherein said B-NHL is relapsed or refractory B-NHL.
10. The method of claim 3, wherein said B-NHL is chronic lymphocytic lymphoma (CLL).
11. The method of claim 1, wherein 24 mg of epcoritamab is administered subcutaneously to the human subject on days 15 and 22 of treatment.
12. The method of claim 11, wherein said B-NHL is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal-zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL), and wherein the patient achieves a complete response (CR).
13. The method of claim 11, wherein said B-NHL is diffuse large B-cell lymphoma (DLBCL).
14. The method of claim 11, wherein said B-NHL is mantle cell lymphoma (MCL).
15. The method of claim 11, wherein said B-NHL is follicular lymphoma (FL).
16. The method of claim 11, wherein said B-NHL is marginal-zone lymphoma (MZL).
17. The method of claim 11, wherein said B-NHL is small lymphocytic lymphoma (SLL).
18. The method of claim 11, wherein said B-NHL is relapsed or refractory B-NHL.
19. The method of claim 11, wherein said B-NHL is chronic lymphocytic lymphoma (CLL).
20. The method of claim 1, wherein said B-NHL is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal-zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL).
21. The method of claim 20, wherein said B-NHL is diffuse large B-cell lymphoma (DLBCL).
22. The method of claim 20, wherein said B-NHL is mantle cell lymphoma (MCL).
23. The method of claim 20, wherein said B-NHL is follicular lymphoma (FL).
24. The method of claim 20, wherein said B-NHL is marginal-zone lymphoma (MZL).
25. The method of claim 20, wherein said B-NHL is small lymphocytic lymphoma (SLL).
26. The method of claim 20, wherein said B-NHL is relapsed or refractory B-NHL.
27. The method of claim 20, wherein said B-NHL is chronic lymphocytic lymphoma (CLL).
28. The method of claim 1, wherein prior to the day 1 of treatment with epcoritamab the human subject has received at least one prior line of treatment for the B-NHL.
29. The method of claim 1, wherein prior to the day 1 of treatment with epcoritamab the human subject has received at least two prior lines of treatment for the B-NHL, in view of Van Den Brink et al. (US 20160333095) in view of Valbjoern (US 20220411505; 8/19/2020) and Mounier et al. (Blood, 2003, 101: 4279-4284, IDS 9/14/2023) as evidenced by Sureda (EMJ Oncol. 2021; 9 [Suppl 8]:2-12 with reference to PeerVoice (20th May 2021)).
The analysis for the reference art set forth above is incorporated.
It would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of the references so as to treat DLBCL patient comprising ani-CD3 and anti-CD20 bispecific antibody (epcoritamab), and the R-CHOP regimen comprising rituximab, cyclophosphamide, doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), and prednisone. One would have been motivated to do so because Van Den Brink and Valbjoern teach a method of treatment of DLBCL cancer in a subject comprising administering an anti-CD3 and anti-CD20 bispecific antibody to the subject; Mounier teaches a method of treating DLBCL comprising administering to a patient in need thereof the R-CHOP regimen. As evidenced by Sureda, RCHOP therapies in combination with other antibody therapies have had mixed results, that epcoritamab in clinical trial status is a putative target therapy to be used in combination with RCHOP.
Thus, by way of the combination of references, one of ordinary skill in the art would have a reasonable expectation of success where the reagents are available for dosing in bioassays and/or animal models for therapeutic regimens in treating DLBCL. It is prima facie obvious to combine two therapeutic agents, each of which is taught by the prior art to be useful for the same purpose, in order to form a combination that is to be used for the very same purpose. The idea of combining the first and second therapeutic agents to form a third flows logically from having the first and second been individually taught in the prior art. See In re Kerkhoven, 205 USPQ 1069 (CCPA 1980); see M.P.E.P. § 2144.06. In this case, both anti-CD3 and anti-CD20 bispecific antibody (EPCO), and the R-CHOP therapy regimen are taught by the prior art for treating DLBCL cancer.
23. Claims 1-3, 12, 15, 17, 20, 23, 26, 29, 33-38, 45-50, and 64-67 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 69, 70, 72-89 and 98-108 of copending Application No. 17/ 923,317 (US 20230227570) in view of in view of Van Den Brink et al. (US 20160333095) in view of Valbjoern (US 20220411505; 8/19/2020) and Mounier et al. (Blood, 2003, 101: 4279-4284, IDS 9/14/2023) as evidenced by Sureda (EMJ Oncol. 2021; 9 [Suppl 8]:2-12 with reference to PeerVoice (20th May 2021)).
Ref claims
1-68. (Canceled)
69. (Currently Amended) A method of treating a B-cell non-Hodgkin lymphoma (B-NHL) in a human subject, the method comprising subcutaneously administering a dose of 0.16 mg of epcoritamab to the subject on day one (1) of treatment and subcutaneously administering a dose of 0.8 mg of epcoritamab to the subject on day eight (8) of treatment,wherein the subject does not experience cytokine release syndrome (CRS) or experiences manageable cytokine release syndrome of grade 1 or grade 2, andwherein after day eight (8) of treatment a dose of 48 mg of epcoritamab is subcutaneously administered in intervals to the subject until progressive disease develops or unacceptable toxicity occurs.
70. (Previously Presented) The method of claim 69, wherein 48 mg of epcoritamab is administered subcutaneously to the human subject on days 15 and 22 of treatment.
71. (Canceled)
72. (Previously Presented) The method of claim 69, wherein said B-NHL is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal-zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL).
73. (Previously Presented) The method of claim 72, wherein said B-NHL is diffuse large B-cell lymphoma (DLBCL).
74. (Previously Presented) The method of claim 72, wherein said B-NHL is mantle cell lymphoma (MCL).
75. (Previously Presented) The method of claim 72, wherein said B-NHL is follicular lymphoma (FL).
76. (Previously Presented) The method of claim 72, wherein said B-NHL is marginal-zone lymphoma (MZL).
77. (Previously Presented) The method of claim 72, wherein said B-NHL is small lymphocytic lymphoma (SLL).
78. (Previously Presented) The method of claim 72, wherein said B-NHL is relapsed or refractory B-NHL.
79. (Previously Presented) The method of claim 72, wherein said B-NHL is chronic lymphocytic lymphoma (CLL).
80. (Previously Presented) The method of claim 69, wherein prior to the day 1 of treatment with epcoritamab the human subject has received at least one prior line of treatment for the B-NHL.
81. (Previously Presented) The method of claim 69, wherein prior to the day 1 of treatment with epcoritamab the human subject has received at least two prior lines of treatment for the B-NHL.
82. (Previously Presented) The method of claim 70, wherein said B-NHL is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal-zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL), and wherein the patient achieves a complete response (CR).
83. (Previously Presented) The method of claim 82, wherein said B-NHL is diffuse large B-cell lymphoma (DLBCL).
84. (Previously Presented) The method of claim 82, wherein said B-NHL is mantle cell lymphoma (MCL).
85. (Previously Presented) The method of claim 82, wherein said B-NHL is follicular lymphoma (FL).
86. (Previously Presented) The method of claim 82, wherein said B-NHL is marginal-zone lymphoma (MZL).
87. (Previously Presented) The method of claim 82, wherein said B-NHL is small lymphocytic lymphoma (SLL).
88. (Previously Presented) The method of claim 82, wherein said B-NHL is relapsed or refractory B-NHL.
89. (Previously Presented) The method of claim 82, wherein said B-NHL is chronic lymphocytic lymphoma (CLL).
90-97. (Canceled)
98. (New) A method of treating a B-cell non-Hodgkin lymphoma (B-NHL) in a human subject, the method comprising administering epcoritamab subcutaneously in 28-day cycles, wherein:a) a priming dose of 0.16 mg is administered on day 1, an intermediate dose of 0.8 mg is administered on day 8, and a full dose of 48 mg is administered on days 15 and 22 of the first cycle;b) a full dose of 48 mg is administered on days 1, 8, 15 and 22 of cycles 2-3;c) a full dose of 48 mg is administered on days 1 and 15 of cycles 4-9; andd) a full dose of 48 mg is administered on day 1 of subsequent cycles until progressive disease develops or unacceptable toxicity occurs.
99. (New) The method of claim 98, wherein said B-NHL is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), follicular lymphoma(FL), marginal-zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL).
100. (New) The method of claim 99, wherein said B-NHL is diffuse large B-cell lymphoma (DLBCL).
101. (New) The method of claim 99, wherein said B-NHL is mantle cell lymphoma (MCL).
102. (New) The method of claim 99, wherein said B-NHL is follicular lymphoma (FL).
103. (New) The method of claim 99, wherein said B-NHL is marginal-zone lymphoma (MZL).
103. (New) The method of claim 99, wherein said B-NHL is marginal-zone lymphoma (MZL).
104. (New) The method of claim 99, wherein said B-NHL is small lymphocytic lymphoma (SLL).
105. (New) The method of claim 99, wherein said B-NHL is relapsed or refractory B-NHL.
106. (New) The method of claim 99, wherein said B-NHL is chronic lymphocytic lymphoma (CLL).
107. (New) The method of claim 98, wherein prior to the day 1 of treatment with epcoritamab the human subject has received at least one prior line of treatment for the B-NHL.
108. (New) The method of claim 98, wherein prior to the day 1 of treatment with epcoritamab the human subject has received at least two prior lines of treatment for the B-NH, in view of Valbjoern (US 20220411505; 8/19/2020) and Mounier et al. (Blood, 2003, 101: 4279-4284, IDS 9/14/2023) as evidenced by Sureda (EMJ Oncol. 2021; 9 [Suppl 8]:2-12 with reference to PeerVoice (20th May 2021)).
The analysis for the reference art set forth above is incorporated.
It would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of the references so as to treat DLBCL patient comprising ani-CD3 and anti-CD20 bispecific antibody (epcoritamab), and the R-CHOP regimen comprising rituximab, cyclophosphamide, doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), and prednisone. One would have been motivated to do so because Van Den Brink and Valbjoern teach a method of treatment of DLBCL cancer in a subject comprising administering an anti-CD3 and anti-CD20 bispecific antibody to the subject; Mounier teaches a method of treating DLBCL comprising administering to a patient in need thereof the R-CHOP regimen. As evidenced by Sureda, RCHOP therapies in combination with other antibody therapies have had mixed results, that epcoritamab in clinical trial status is a putative target therapy to be used in combination with RCHOP.
Thus, by way of the combination of references, one of ordinary skill in the art would have a reasonable expectation of success where the reagents are available for dosing in bioassays and/or animal models for therapeutic regimens in treating DLBCL. It is prima facie obvious to combine two therapeutic agents, each of which is taught by the prior art to be useful for the same purpose, in order to form a combination that is to be used for the very same purpose. The idea of combining the first and second therapeutic agents to form a third flows logically from having the first and second been individually taught in the prior art. See In re Kerkhoven, 205 USPQ 1069 (CCPA 1980); see M.P.E.P. § 2144.06. In this case, both anti-CD3 and anti-CD20 bispecific antibody (EPCO), and the R-CHOP therapy regimen are taught by the prior art for treating DLBCL cancer.
This is a provisional nonstatutory double patenting rejection.
Conclusion
24. No claims are allowed.
25. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643