DETAILED NOTICE
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 .
Priority
The present Application, filed December 13, 2022 claims the benefit of U.S. Provisional Patent Application No. 63/267,254, filed January 28, 2022. The present Application also claims priority to Indian Patent Application No. 202123060432, filed December 23, 2021.
Status of the Claims
In the amendment filed March 4, 2026, claims 24-25 are canceled and claim 22 is amended. Claims 22-23 are currently pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on March 4, 2026 is acknowledged.
Declaration Under 37 C.F.R. § 1.132
The Declaration of Dr. Jeffrey Herzfeld, submitted March 4, 2026 (hereinafter, “the Herzfeld declaration”), under 37 C.F.R. § 1.132 is acknowledged.
Previous Rejections and/or Objections
Claim Objections:
The objection to claim 22 is obviated by the amendment to claim 22, and this objection is therefore withdrawn.
Rejections for Indefiniteness:
The cancelation of claims 24-25 renders rejection of these claims moot. The amendment to claim 22 resolves the rejections to claims 22-23 under 35 U.S.C. § 112(b) for indefiniteness, and these rejections are withdrawn.
Rejections for nonstatutory double patenting:
The previous provisional rejections for nonstatutory double patenting over U.S. Patent Application No. 17/014, 604 are obviated by the abandonment of the reference application. These rejections are accordingly withdrawn.
Response to Amendments/Arguments
Claim Rejections-- 35 USC § 103 – Modified in View of Amendment
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 22-23 are obvious over Heritage, Reddy, Micetich, Przepiorka, and Benekli:
Claims 22-25 are rejected under 35 U.S.C. § 103 as being unpatentable over the non-patent publication Highlights of Prescribing Information for BiCNU (carmustine), pgs. 1-12 (2017) by Heritage Pharmaceutical (hereinafter, “Heritage”), in view of U.S. Patent Application Publication No. 2019/0070136 to Reddy et al. (hereinafter, “Reddy”), further in view of the non-patent publication, Phase I Study of Streptozocin and Carmustine-Sequenced Administration in Patients With Advanced Cancer, J. Nat. Canc. Inst., 84, pg. 256-261 (1992) by Micetich et al. (hereinafter, “Micetich”), further in view of the non-patent publication, Carmustine, etoposide, cytarabine and melphalan as a preparative regimen for allogeneic transplantation for high-risk malignant lymphoma, Ann. Oncol., 10, pgs. 527-532 (1999) by Przepiorka et al. (hereinafter, “Przepiorka”), further in view of the non-patent publication, Intensive conditioning regimen of etoposide (VP-16), cyclophosphamide and carmustine (VCB) followed by autologous hematopoietic stem cell transplantation for relapsed and refractory Hodgkin's lymphoma, Bone Marrow Transpl., 41, pgs. 613-619 (2008) by Benekli et al. (hereinafter, “Benekli”).
In Applicant’s Remarks of March 4, 2026, citing the Herzfeld declaration, Applicant cites several advantages of the claimed method as evidence of nonobviousness. Applicant, citing the Herzfeld declaration, asserts that the claimed method 1) eliminates a step in carmustine reconstitution relative to approved carmustine formulations; 2) replaces the ethanol associated with infusion related reactions with propylene glycol; and 3) dramatically reduces the infusion time. This three-part statement of advantages, stated in paragraph 7 of the Herzfeld declaration recapitulates a point made in paragraphs 5-7 of the Herzfeld declaration.
With respect to asserted advantage 1, while the prior art method of Heritage does dictate a two-step dilution, there is nothing of record to suggest that two-step dilution would have been understood as clinically or chemically necessary. Rather, knowledge in the art suggests that it was utilized as a convenience. The non-patent publication, Preformulation Studies with 1,3-Bis(2-chloroethyl)-1-nitrosourea, Ph.D. Thesis, February 19, 1974, Oregon State University, by Laskar (hereinafter, “Laskar”) included on IDS submitted 12/13/2022, teaches that dissolution of BCNU (carmustine) into aqueous solvents is slow (pgs. 75-76), and also that carmustine is generally unstable in aqueous solution, particularly when little organic cosolvent is present (Table IX, pg. 50). As such, preparing a preliminary, concentrated, organic/aqueous solution of carmustine that can be stored under refrigeration for up to 24 hours (Heritage) confers a particular convenience over the alternative of preparing the for-use aqueous solution immediately prior to administration, but would not have been understood as a clinical or chemical necessity.
With respect to asserted advantage 2, as described in the previous and current office action, this is taught by Micetich (and is also taught by Laskar). While, as noted in Applicant’s Remarks and the Herzfeld declaration, Micetich expressly teaches one hour infusion, not thirty minute infusion, as explained in the reasons for rejection, one of ordinary skill in the art would have had a reasonable expectation of success in shortening or otherwise optimizing the 1 hour infusion time of Micetich to improve convenience. While not expressly cited in the reasons for rejection, such impetus to further optimize the shortened infusion time of Micetich is only bolstered by the teaching of Laskar that BCNU-propylene glycol formulation could be administered by slow intravenous “push” rather than fast drip (pg. 51).
With respect to asserted advantage 3, as explained in the reasons for rejection, this element is taught by Reddy (and, while not expressly cited in the reasons for rejection, by Laskar).
The Herzfeld declaration states (paragraph 8) that these benefits, such as reduced infusion time while avoiding the reactions known to be associated with rapid infusion of carmustine prepared from an ethanol reconstitution, are evidence by an ongoing Phase II trial. Even if this were true, however, it would not eliminate the fact that these benefits were foreseeable over the art, as described above. Furthermore, while a clinical trial may produce evidence of benefits, the existence of the trial is not, in and of itself, evidence of benefits.
In paragraphs 10-11, the Herzfeld declaration points out elements that Heritage and Reddy do not teach, but these are elements for which neither is cited. For example, Heritage is not cited as teaching alternative formulations. In paragraph 11, the Herzfeld declaration notes that no real examples of Reddy utilize 100% propylene glycol as reconstitution solvent. However, Reddy plainly discloses that propylene glycol can be utilized as a sole reconstitution solvent (a teaching that is echoed by Laskar, although the latter is not expressly cited in the reasons for rejection).
Finally, Applicant, citing paragraph 12 of the Herzfeld declaration, questions the aptness of Micetich, noting that Micetich addresses shorter infusion times in a different context – coadministration with an agent that is not utilized in the present methods. However, given that the existing limitation on shorter infusion times results from reactions to rapidly infused ethanol/carmustine formulations, the respects in which the context of Micetich differ from the instant method do not appear to be relevant to infusion rate. As such, the rapid infusion of Micetich is regarded as relevant to the presently claimed method. Furthermore, as noted, Laskar also supports shorter infusion times, although Laskar is not expressly cited in the reasons for rejection at this time. Applicant and the Herzfeld declaration also note that Micetich deals with lower carmustine doses. While the elevated dose of carmustine is newly added to claim 22 by amendment, this element is taught by Benekli, as discussed below.
For the aforementioned reasons, the rejections for obviousness, as modified to account for the claim amendments, are reiterated.
Modified rejections:
Claim 22 recites a method for administering carmustine to a subject in need thereof comprising administering, by intravenous infusion over about 30 minutes, an administrable solution of carmustine. The administrable solution is prepared from a kit comprising a product vial containing 50 mg to 600 mg of lyophilized carmustine, and a diluent vial containing 6-18 mL of sterile propylene glycol, the kit being stored at 2-8 °C. Claim 22 further recites that the administrable solution is prepared by:
allowing the diluent vial to attain room temperature
aseptically removing the propylene glycol from the diluent vial, injecting it into the product vial containing lyophilized carmustine, and shaking the product vial to dissolve the lyophilized carmustine to form a reconstituted solution, wherein the amount of propylene glycol injected in the product vial is 3 mL per 100 mg of carmustine
storing the reconstituted solution and prior to performing step (d), the stored reconstituted solution is examined for crystal formation and if crystals are observed, they are re-dissolved by warming the reconstituted solution to room temperature with agitation
diluting the reconstituted solution with an aqueous 0.9% NaCl solution or an aqueous 5% dextrose solution to obtain the administrable solution, wherein the concentration of carmustine in the administrable solution is up to about 3.1 mg/mL.
Claim 22 further recites wherein the subject has relapsed or refractory Hodgkin lymphoma or Non-Hodgkin Lymphoma and the carmustine is administered to the subject as part of a regimen with etoposide, cytarabine, and melphalan, and the combination is administered prior to autologous hematopoietic cell transplantation. As now amended, claim 22 further recites wherein the carmustine is administered at a dosage of 300 mg/m2.
Heritage teaches, inter alia, methods for preparing and administering BiCNU (carmustine for injection). The methods include intravenous infusion of lyophilized carmustine after reconstitution (pg. 9, section 11, Description) an intravenous solution of carmustine, involving dissolution of carmustine in dehydrated alcohol, dilution in water, and further dilution in aqueous NaCl or 5% dextrose (section 2.2, pg. 4). Heritage teaches that the injectable solution (administrable solution) is prepared from a kit having 100 mg of lyophilized carmustine in a first single-dose vial, and 3 mL of sterile diluent (e.g. dehydrated alcohol) in a second single-dose vial (pg. 5, section 3 DOSAGE FORMS AND STRENGTHS), and that the vials should be stored at 2-8 °C (top of pg. 13).
Heritage teaches aseptically removing the sterile diluent (i.e. the dehydrated alcohol) with the help of a sterile syringe, and injecting the sterile diluent into the vial containing the carmustine (illustrated instructions, pg. 12).
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Above: partial illustrated instructions from pg. 12 of Heritage.
Heritage further teaches that after reconstitution, the carmustine solution should be examined for the presence of crystals prior to use, and that any such crystals can be redissolved by warming the vial to room temperature along with agitation (pg. 4, section 2.2 Preparation and Administration of Intravenous Solution). From this, one of ordinary skill in the art would understand that warming an incompletely dissolved carmustine solution/mixture facilitates complete dissolution. As such, it would have been obvious to one of ordinary skill in the art to warm the solvent prior to mixing in order to facilitate complete dissolution of the mixture to render it suitable for use. Furthermore, the agitation taught by Heritage can constitute both the “agitation” of instant step c and the “shaking” of instant step b.
Heritage teaches that the reconstituted solution is further diluted with 500 mL NaCl Injection, USP or 5% Dextrose Injection, USP to a concentration of 0.2 mg/mL (a concentration that is “up to” about 3.1 mg/mL) prior to infusion (pg. 4, section 2.2 Preparation and Administration of Intravenous Solution). Heritage further teaches that BiCNU is a therapy for relapsed or refractory Hodgkin’s lymphoma, in combination with other drugs (pg. 1, INDICATIONS AND USAGE).
Heritage thus teaches a method of administering carmustine to a subject in need thereof comprising administering by intravenous infusion an administrable solution of carmustine comprising a product vial containing 50 mg to 600 mg of lyophilized carmustine and a diluent vial containing sterile organic solvent, the kit being stored at 2-8 °C. As described above, Heritage also teaches
allowing the diluent vial to attain room temperature;
aseptically removing the organic solvent from the diluent vial, injecting it into the product vial containing lyophilized carmustine, and shaking the product vial to form a reconstituted solution wherein the volume of organic solvent is 3 mL per 100 mg of carmustine;
storing the reconstituted solution and prior to performing step (d), examining the reconstituted solution for crystal formation and if crystals are observed, re-dissolving said crystals by warming the reconstituted solution to room temperature with agitation; and
diluting the reconstituted solution with aqueous 0.9% NaCl or aqueous 5% dextrose to obtain the administrable solution having up to about 3.1 mg/mL carmustine.
Heritage does not teach (i) that the organic solvent for reconstitution is propylene glycol (it is dehydrated alcohol in Heritage); (ii) that administration is over (for a period of) about 30 minutes to about 1 hour; (iii) that the carmustine is administered to the subject as part of a regimen with etoposide, cytarabine, and melphalan, wherein the drugs are administered prior to autologous hematopoietic cell transplantation; or (iv) that the diluent vial contains 6-18 mL of organic solvent. Heritage also does not teach the subject attributes, numbered (i)-(ix), added to claim 1 in the most recent amendment. All of these additional elements would have been obvious, as each of them was known in the art. See, for example, Reddy, Micetich, Przepiorka, and Benekli.
Regarding the use of propylene glycol, Reddy teaches a method of treating a patient, the method comprising diluting and administering a liquid parenteral composition to the patient, the composition including carmustine and one or more organic solvents selected from propylene glycol and five other nonaqueous solvents (claims 1 and 7). Reddy explicitly teaches that the parenteral composition includes carmustine and one or more solvents selected from propylene glycol, dehydrated alcohol, and several others (paragraph [0013]), and that propylene glycol, dehydrated alcohol, and six other solvents constitute the “preferred solvents” (paragraph [0027]). Thus, while the real examples of Reddy that have propylene glycol as solvent generally include it in combination with another solvent such as N,N Dimethylacetamide (e.g. Examples 1 and 2), Reddy clearly states that any of the preferred solvents, including propylene glycol, can be used as the sole organic solvent. It thus would have been obvious to one of ordinary skill in the art to replace the dehydrated alcohol of Heritage with the propylene glycol of Reddy, since Reddy teaches propylene glycol and dehydrated alcohol as being equivalent, or at least comparable, solvents for use in a ready-to-use parenteral solution of carmustine.
Regarding the limitation wherein the carmustine is administered over about 30 minutes to an hour, Micetich teaches a clinical phase I study of the effects of infusion of BCNU (carmustine) after infusion of streptozocin in cancer patients (Abstract). In particular, Micetich teaches that carmustine dose levels were at 100-150 mg/m2 (i.e. about 175-260 mg dose for a 1.75 m2 person), dissolved in 150 mL of 5% aqueous dextrose (pg. 257, right column, third full paragraph), i.e. about 1.17 to about 1.73 mg/mL carmustine in the infusion solution, and that the aqueous carmustine/dextrose was administered intravenously for 1 hour (pg. 257, right column, third full paragraph). It would have been obvious to administer the carmustine solution of Heritage/Reddy in 1 hour because, according to the teachings of Micetich, this was known to be a safe and effective means for intravenous infusion of carmustine.
Regarding the limitation that the carmustine is administered to the subject as part of a regimen with etoposide, cytarabine, and melphalan, wherein the drugs are administered prior to autologous hematopoietic cell transplantation, Przepiorka teaches that the combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) is an effective autologous transplantation preparative regimen for lymphoma. It thus would have been obvious to utilize a BEAM regimen as taught by Przepiorka as preparation for (prior to) autologous hematopoietic cell transplantation.
With respect to the limitation that the volume of diluent in the diluent vial is 6-18 mL, Heritage teaches that the diluent vial contains 3 mL of diluent (dehydrated alcohol, in the case of Heritage). However, the concentration of carmustine in diluent is the same in Heritage as in claim 22 (3 mL diluent per 100 mg of carmustine). Thus if the carmustine vial held 100 mg, as specified in Heritage and allowed in instant claim 22, only 3 mL of diluent would be utilized and the additional diluent of instant claim 22 would merely be unused, superfluous diluent. In any event, it would be obvious to adjust the volume of diluent as desired to enable preparation of the 3 mL diluent per 100 mg carmustine reconstituted solution, as taught by Heritage, regardless whether all the diluent is used or not.
With respect to the limitation that the carmustine is administered at a dosage of 300 mg/m2, Micetich teaches that carmustine dose levels were at 100-150 mg/m2 (pg. 257, right column, third full paragraph), and none of Heritage, Reddy, Micetich, or Przepiorka expressly teaches the higher dosage of 300 mg/m2. However it would have been obvious to utilize such a dosage because high doses of carmustine was known in the art to be effective and well-tolerated for the treatment of refractory Hodgkin lymphoma. See, for example, Benekli.
Benekli teaches a study of high dose, 600 mg/m2 carmustine in conjunction with cyclophosphamide and etoposide (Abstract) of 43 subjects having relapsed or refractory Hodgkin’s lymphoma (Patients and methods, first paragraph). Benekli teaches that 86% of patients achieved or maintained a complete remission under this regimen (pg. 615, left column, Results, second paragraph), concluding that this “intensified” regimen is well-tolerated and highly effective for the treatment of relapsed or refractory Hodgkin’s lymphoma (pg. 617, left column, final paragraph of Discussion). On this basis, one would have been motivated to try an elevated dose of carmustine in the method of Heritage, Reddy, Micetich, or Przepiorka and would have had a reasonable expectation of success in obtaining effective treatment of Hodgkin’s lymphoma with minimal additional toxicity.
Heritage, as modified by Reddy, Micetich, Przepiorka, and Benekli, thus teaches all elements of claim 22.
With respect to claim 23, Micetich teaches that carmustine dose levels were at 100-150 mg/m2 (i.e. about 175-260 mg dose for a 1.75 m2 person), dissolved in 150 mL of 5% aqueous dextrose (pg. 257, right column, third full paragraph), i.e. about 1.17 to about 1.73 mg/mL carmustine in the infusion solution. Furthermore, as noted above, the administrable solution of Heritage is at 0.2 mg/mL (section 2.2), which is “up to 3.06 mg/mL.”
Double Patenting – Newly Applied
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 22-23 are provisionally rejected for nonstatutory double patenting over the ’740 application in view of Heritage, Micetich, Przepiorka, and Benekli:
Claims 22-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 19/267,740 (hereinafter, “the ’740 application”), in view of Heritage, Micetich, Przepiorka, and Benekli. For the ’740 application, see the corresponding U.S. Patent Application Publication No. 2025/0339390.
Both the instant claims and those of the ’740 application are directed to methods for preparing administrable carmustine and administering carmustine to a patient in need thereof. Claims 1-19 of the ’740 application recite methods for administering carmustine to a patient, although the method steps only pertaining to preparing the administrable solution. The solution preparation steps correspond to those of the instant claims. The aspects of actually administering the solution to the patient are an obvious extension of this, in view of the teachings of Heritage, Micetich, Przepiorka, and Benekli, as discussed above.
This is a provisional rejection.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ALEXANDER K. SHOWALTER/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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