Claim Objections
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 .
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Election/Restrictions
Applicant's election with traverse of tartaric acid as the stabilizer species, polysorbate as the solubilizer species, water for injection as the vehicle, monothioglycerol as the elected antioxidant, and EDTA as the elected chelating agent in the reply filed on 10/27/2025 is maintained.
Priority
This application is a continuation of U.S. Application No. 18/794,778 filed August 5, 2024, which in turn is a continuation of U.S. Application No. 18/069,204 filed December 12, 2022, issued as U.S. Patent No. 12,097,197 B2 on September 4, 2024, which in turn claims the benefit of Indian Patent Application No. 202141059731 filed December 21, 2021.
Claims Status
Claims 1-14, 16-17, 19, and 21-23 are pending. Claims 15, 18, 20, are canceled. Claims 4 and 7 are withdrawn. Claims 1-3, 5-6, 8-19, and 21-23 are examined in accordance to the elected species.
Action Summary
Objection to the specification is withdrawn in light of Applicant’s argument that Akynzeo® is properly accompanied with the generic terminology on page 3, last paragraph of the specification.
The object to claims 1, 3, 12, and 13 is withdrawn in light of the amendment to claim 1 and 12.
Claims 1-3, 5-6, and 8-11 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are withdrawn in light of the amendment to claim 1 and 12. However, claims 12-14, and 16-17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are maintained, but modified and revisited to include new claims 22 and 23.
Claims 1-3, 5-6, 8-13, and 16-17 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, are withdrawn, but modified and revisited to include claim 18 and other claims that were inadvertently omitted. The rejection was withdrawn because the Applicant argued that claim 18, which did not form the basis of the rejection is now incorporated into the independent claims 1 and 12, thereby rendering the rejection moot.
Claim 1-3, 5-6, and 8-11 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, are withdrawn, but modified and revested to include claim 18 and other claims that were inadvertently omitted. The rejection was withdrawn because the Applicant argued that claim 18, which did not form the basis of the rejection is now incorporated into the independent claims 1 and 12, thereby rendering the rejection moot.
Claims 12, 13, and 15-20 are rejected under 35 U.S.C. 103 as being unpatentable over Chandrashekhar (US2020/0188368 A1) in view of Renzo et al (Bone Marrow Transplantation (2020) 55:2114–2120), are maintained, but revisited and modified in light of the claim amendment.
Claims 1-3, 5-6, and 8-20 rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 12,097,197, are maintained, but revisited and modified in light of the claim amendment.
Claims 1-3, 5-6, and 8-20 rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 12,370,190B2, are maintained, but revisited and modified in light of the claim amendment.
12-14, 16-17, are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are maintained, but modified and revested to include new claims 22 and 23.
Acknowledgement is made of the receipt and entry of the amendment to the claims and arguments/remarks, filed on December 09, 2024.
New Objection necessitated by claim amendment
Claim Objections
Claims s 1-3, 5-6, 8-11, and 21 are objected to because of the following informalities: claim 1 recites “about 0.5 mg/mL to about 22 mg/mL of a pharmaceutically acceptable stabilizer is selected from an organic acid, an inorganic acid and a mixture thereof.” There is a grammatical issue with part (b) of claim 1. The “is” after stabilizer should simply be removed. Removing the extra “is” will make the sentence correct and clear. Appropriate correction is required.
Maintained Rejection
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 12-14, 16-17, 22-23 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.
With respect to claims 12 and 19, the recitation “mixtures thereof” renders the claim indefinite because the metes and bounds of mixtures thereof cannot be determined. For example, mixtures thereof can encompass a mixture of different organic acid or a mixture of different inorganic acid, or a mixture of organic acid and inorganic acid. It is not clear what is encompassed by mixtures of inorganic acid, or mixtures of organic acid, and mixtures of organic and inorganic acid. The specification does not provide a stander for ascertain the requisite degree, and one of ordinary skill in the art would not reasonably apprise of the scope of mixtures.
Applicants argue that in view of the amendment of the term “mixtures thereof” to the term “a mixture thereof” renders the rejection moot. However, the Examiner notes the Applicant’s partial amendments replacing “mixtures thereof” with “a mixture thereof.” However, claims 12 and claim 19 still retain “mixtures thereof,” which perpetuates the original issue. For clarity and consistency, the Examiner requests that all claims align to a single, clear phrase.
Modified and Revisited Rejection
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a)IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same,and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 12-14, and 16-17 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. While Applicant is in possession of
(1) a stable injectable pharmaceutical solution comprising: comprising
19.75 mg/ml netupitant,
300 mg/ml ethanol,
0.25-0.45 mg/ml polysorbate 80,
10 mg/ml TRIS or the absence of TRiS,
10-60 mg/ml phosphoric acid,
100-110 mg/ml propylene glycol, and
water for injection at a pH of 2.54 to 5.97 that is stable for up to 24-72 hours;
(2) a stable injectable solution comprising
(1) a stable injectable pharmaceutical solution comprising: comprising
15.192-19.75 mg/ml netupitant,
0.0215-0.028 mg/ml palonosetron Hcl
230-300 mg/ml ethanol,
0.192-0.25 mg/ml polysorbate 80,
5.41 mg/ml tartaric acid, or 2.167 mg/ml aspartic acid, or 15-20 mg/ml phosphoric acid,
76.923-100 mg/ml propylene glycol, and
water for injection at a pH of 4.3 to 6.0 that is stable for up to 24 hours; and
(3) a stable injectable pharmaceutical solution comprising: comprising
13.13-15.20 mg/ml netupitant,
0.0014-0.022 mg/ml palonosetron Hcl
8.333-230.7 mg/ml ethanol,
12.50-192.3 mg/ml polysorbate 80, or 76.92 mg/ml propylene glycol,
0.8-12.00 mg/ml citric acid anhydrous, 0.267-4.00 mg/ml tartaric acid, and 0.008-0.3 mg/ml L-aspartic acid,
0.25-0.5 mg/ml monothioglycerol, 0.18-0.36 mg/ml sodium thiosulfate, 0.1-0.2 mg/ml sodium formaldehyde sulfoxylate, or 1.25 mg/ml ascorbic acid
6.667-40 mg/ml HPβCD,
0.284-0.32 mg/ml EDTA, and
water for injection at a pH of 2.8-5.0 that is stable for 2 months at 25oC/60%RH and 1 week at 60oC, Applicant is not in possession of
(i) a stable injectable solution comprising:
(a) netupitant at a concentration of about 1.975 mg/mL as the only active ingredient;
(b) about 0.5 mg/mL to about 22 mg/mL of a pharmaceutically acceptable stabilizer selected from an organic acid, an inorganic acid and a mixture thereof;
(c) about 0.1 mg/mL to about 290 mg/mL of a pharmaceutically acceptable solubilizer selected from the group consisting of cyclodextrin. cyclodextrin derivative. polysorbate, propylene glycol and a mixture thereof; and
(d) at least one pharmaceutically acceptable vehicle, wherein the solution has a pH ranging from 2 to 6, and wherein the solution is suitable for intravenous administration; and
(ii) a stable injectable pharmaceutical solution comprising:
(a) netupitant at a concentration of about 0.5 mg/mL to about 20 mg/mL and palonosetron hydrochloride at a concentration of about 0.001 mg/ml to about 0.1 mg/mL as the only active ingredients;
(b) about 0.5 mg/mL to about 22 mg/mL of a pharmaceutically acceptable stabilizer selected from an organic acid, an inorganic acid, and amixture thereof;
(c) about 0.1 mg/mL to about 290 mg/mL of a pharmaceutically acceptable solubilizer selected from the group consisting of cyclodextrin, cyclodextrin derivative, polysorbate, propylene glycol and a mixture thereof; and
(d) at least one pharmaceutically acceptable vehicle, wherein the solution has a pH ranging from 2 to 6, and wherein the solution is suitable for intravenous administration; and
(ii) a stable injectable pharmaceutical solution comprising:
(a) netupitant at a concentration of about 1.975 mg/mL and palonosetron hydrochloride at a concentration of about 0.0028 mg/ml as the only active ingredients;
(b) about 0.5 mg/mL to about 22 mg/mL of a pharmaceutically acceptable stabilizer selected from an organic acid, an inorganic acid, and amixture thereof;
(c) about 0.1 mg/mL to about 290 mg/mL of a pharmaceutically acceptable solubilizer selected from the group consisting of cyclodextrin, cyclodextrin derivative, polysorbate, propylene glycol and a mixture thereof; and
(d) at least one pharmaceutically acceptable vehicle, wherein the solution has a pH ranging from 2 to 6, and wherein the solution is suitable for intravenous administration.
The Written Description Guidelines for examination of patent applications indicates, “the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show applicant was in possession of the claimed genus.” (Federal register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001, see especially page 1106 column 3) and (see MPEP 2164).
In the instant case, independent claim 1 is directed to a stable injectable solution comprising:
(a) netupitant at a concentration of about 0.5mg/mL to about 20 mg/mL as the only active ingredient;
(b) at least one pharmaceutically acceptable stabilizer at a concentration ranging from about 0.5 mg/mL to about 22 mg/mL, wherein the pharmaceutically acceptable stabilizer is an organic acid, inorganic acid and mixtures thereof;
(c) at least one pharmaceutically acceptable solubilizer at a concentration of about 0.1 mg/mL to about 290 mg/mL, wherein the pharmaceutically acceptable solubilizer is selected from the group consisting of cyclodextrin. cyclodextrin derivative. polysorbate, propylene glycol and a mixture thereof; and
(d) at least one pharmaceutically acceptable vehicle, wherein the solution has a pH ranging from 2 to 6, and wherein the solution is suitable for intravenous administration and independent claim 12 is directed to a stable injectable pharmaceutical solution comprising:
(a) netupitant at a concentration of about 0.5 mg/mL to about 20 mg/mL and palonosetron hydrochloride at a concentration of about 0.001 mg/ml to about 0.1 mg/mL as the only active ingredients;
(b) at least one pharmaceutically acceptable stabilizer at a concentration ranging from about 0.5 mg/mL to about 22 mg/mL wherein the pharmaceutically acceptable stabilizer is organic acid, inorganic acid and mixtures thereof;
(c) at least one pharmaceutically acceptable solubilizer at a concentration of about 0.1 mg/mL to about 290 mg/mL selected from the group consisting of cyclodextrin, cyclodextrin derivative, polysorbate, propylene glycol and a mixture thereof. Therefore, the claims encompass a genus of compositions defined by its physicochemical property (stable or stability), which is simply a wish to know the identity of such composition that will satisfy its physicochemical property.
Accordingly, there is insufficient written description encompassing the broad range of about 0.5mg/mL to about 20 mg/mL netupitant as the only active ingredient, the broad range of netupitant at a concentration of about 0.5 mg/mL to about 20 mg/mL and palonosetron hydrochloride at a concentration of about 0.001 mg/ml to about 0.1 mg/mL as the only active ingredients, the broad range of about 0.5 mg/mL to about 22 mg/mL of any organic acid, any inorganic acid and any mixtures thereof as a stabilizer, the broad recitation of organic acid, inorganic acid, and mixtures thereof, the broad range of about 0.1 mg/mL to about 290 mg/mL of a pharmaceutically acceptable solubilizer is selected from the group consisting of cyclodextrin. cyclodextrin derivative, polysorbate, propylene glycol and a mixture thereof; the broad recitation of at least one pharmaceutically acceptable vehicle, and the broad recitation of cyclodextrin and cyclodextrin derivative that give rise to a stable injectable solution. The relevant identifying characteristics of the genus such as structure or other physical and/or chemical characteristics of stable injectable solution as disclosed in the claims are not set forth in the specification as-filed, commensurate in scope with the claimed invention. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed” (see page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (see Vas-Cath at page 1116).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Thus, the specification fails to describe these DNA sequences. The Court further elaborated that generic statements are not adequate written description of the genus because it does not distinguish the claimed genus from others, except by function.
Per the Enzo court’s example, (Enzo Biochem., Inc. v. Gen-Probe Inc., 63 USPQ2d 1609 (CA FC 2002) at 1616) of a description of an anti-inflammatory steroid, i.e., a steroid (a generic structural term) couched “in terms of its function of lessening inflammation of tissues” which, the court stated, “fails to distinguish any steroid from others having the same activity or function” and the expression “an antibiotic penicillin” fails to distinguish a particular penicillin molecule from others possessing the same activity and which therefore, fails to satisfy the written description requirement. Similarly, the claimed stable injectable solution does not distinguish any particular inactive ingredients such as inorganic acid, organic acid, cyclodextrin, cyclodextrin derivative, polysorbate, propylene glycol, and at least on pharmaceutically acceptable vehicle from other compositions having the same activity or function and as such does not satisfy the written-description requirement. Applicant has not disclosed enough relevant, identifying characteristics, such as structure or other physical and/or chemical properties, sufficient to show possession of the claimed genus. Mere idea or function is insufficient for written description; isolation and characterization at a minimum are required. A description of what a material does, rather than what it is, usually does not suffice. Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
M.P.E.P. 2163 II-A-3-a ii) states: “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i) (C), above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004) (Claims directed to PTFE dental floss with a friction-enhancing coating were not supported by a disclosure of a microcrystalline wax coating where there was no evidence in the disclosure or anywhere else in the record showing applicant conveyed that any other coating was suitable for a PTFE dental floss.)”.
In the instant case, Applicants disclose only injectable solutions comprising 19.75 mg/ml netupitant, 300 mg/ml ethanol, 0.25 mg/ml polysorbate 80, 10 mg/ml TRIS, 20 mg/ml phosphoric acid, 100 mg propylene glycol, and water for injection at a pH of 3.05 to 5.97 that last up to 28-72 hours and an injectable solutions comprising 13.13 mg/ml netupitant, 0.186 mg/ml palonosetron Hcl, 125 mg/ml ethanol, 190 mg/ml polysorbate 80, 12.00 mg/ml citric acid anhydrous, 4.0 mg/ml tartaric acid, 1.12 mg/ml L-aspartic acid, 100 mg/ml HPβCD, 4.26 mg/ml EDTA, and water for injection at a pH 5 that is stable for 2 months. The stability data provided for said solution that has netupitant and palonosetron as the only actives shows the solution is stable for 2 months and the one with only netupitant is only stable for up to 72 hours. However, the Examiner notes that the data provided in comparison injectable solution comprising 19.75 mg/ml netupitant, 300 mg/ml ethanol, 0.45 mg/ml polysorbate 80, 10 mg/ml TRIS, 60 mg/ml phosphoric acid, 100 mg propylene glycol, and Milli-Q water at a pH of 2.54 and 2.60 was stable for up to 28 hours, which also meets the instantly claimed physiochemical properties. It is noted that there is no injectable solution with different inorganic/organic acid or mixtures of acids other than phosphoric acid, different stabilizers as a single stabilizer or mixture of stabilizer other polysorbate 80 and propylene glycol, and different pharmaceutically acceptable vehicle other than ethanol and water. In fact, the selection of the specific organic acid and polysorbate can significantly change the stability of injectable solutions due to their differing chemical properties and degradation pathways. For example, polysorbate 80 (PS80) vs. polysorbate 20 (PS20): PS80 has a higher content of monounsaturated fatty acids (oleic acid), while PS20's main component is saturated lauric acid, which may have an effect on stability. In sum, the specific type and concentration of both organic/inorganic acids, polysorbates, antioxidant, and chelator, and pH must be carefully selected during formulation development to ensure the long-term physical and chemical stability of injectable solutions. These selections are protein-specific and require thorough characterization to optimize the final drug product.
Given the broad scope of the claimed subject matter of the large genus of injectable solution comprising the broad range of each ingredient, the broad genus of inorganic acid, organic acid, and mixtures thereof, the broad genus of cyclodextrin, cyclodextrin derivative, polysorbate, propylene glycol and a mixture thereof, and the broad genus of at least one pharmaceutical acceptable vehicle thereof that might satisfy the instantly claimed physicochemical properties), applicant has not provided sufficient written description that would allow the skilled artisan to recognize that applicant was in possession of the stable injectable solution genus claimed.
In the absence of structural characteristics that are shared by members of the broad range of each ingredient, the broad genus of inorganic acid, organic acid, and mixtures thereof, the broad genus of cyclodextrin, cyclodextrin derivative, polysorbate, propylene glycol and a mixture thereof, and the broad genus of at least one pharmaceutical acceptable vehicle thereof, which has the stability properties claimed one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus. Thus, Applicant was not in possession of the claimed genus. See University of California v. Eli Lilly and Co. 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997).
In summary, the skilled in the art will not know which other components (if any) and in which proportion should be present in the claimed injectable solution in order to satisfy the stability of the solution.
Applicant argues that because claims 15, 18, and 19 have not been rejected for failing to comply with the written description, Applicant has amended claim 1 to incorporate the limitation of claim 18.
In response, although, the previous rejection has been withdrawn based on the amendment to claim 1, the revisited and modified rejection now addresses the concern of incorporating claim 18, which had previously been inadvertently omitted in the rejection.
Modified and Revisited Rejection
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 non-obviousness.
Claims 1-3, 5-6, 8-19, and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Chandrashekhar (US2020/0188368 A1) in view of Renzo et al (Bone Marrow Transplantation (2020) 55:2114–2120).
Chandrashekhar teaches a parenteral formulation for a method of treating chemotherapy-induced nausea and vomiting comprising:
i. Palonosetron hydrochloride
ii. NK1 receptor antagonist selected from the group comprising Fosaprepitant, Aprepitant, Rolapitant and Netupitant
iii. Corticosteroid selected from Dexamethasone and Methylprednisolone and
iv. Pharmaceutically acceptable excipients. (See paragraph [0041], claims 15 and claim
1.) In particular, Chandrashekhar teaches one the following liquid composition:
No
Ingredients
Quantity/mL (mg)
1.
Aprepitant
15
mg
2.
Dexamethasone Sodium
1.20
mg
Phosphate
3.
Palonosetron
0.025
mg
4.
Castor Oil
50.00
mg
5.
Polysorbate-80
40.00
mg
6.
Glycerine
22.00
mg
7.
Sorbic acid
1.00
mg
8.
Sodium acetate
0.50
mg
9.
Boric acid
1.00
mg
10.
Sodium EDTA
0.20
mg
11.
Sodium Hydroxide/
Q. s
Hydrochloric acid
12.
Water for Injection
Q.s to 1 ml
(See Example 5.) Additionally, Chandrashekhar teaches the one or more pharmaceutically acceptable excipients are selected from the group consisting of stabilizing agents, solubilizing agents, buffering agents, pH adjusting agents and solvents, wherein the total impurities are less than 10% w/w, when stored at 2-8° C. (See claims 2-4.) The parenteral formulation is a stable formulation. (See paragraph [0035].) The solution is suitable for intravenous administration. Moreover, Chandrashekhar teaches the pH ranges from 4 to 12. (See claim 12.) Chandrashekhar teaches the concentration of Netupitant ranges from about 0.5 mg/ml to 100 mg/ml and the concentration of Palonosetron ranges from about 0.0005 mg/ml to 5 mg/ml. (See paragraph 0063].) The formulations can be administered as a ready to use solution; ready to dilute solution; lyophilized formulation; suspension, emulsion and the like. (See paragraph [0067].) Chandrashekhar teaches suitable buffers include tartrate (salt of tartaric acid) or acetate or salt thereof. (See paragraph [0053.). Suitable stabilizing and solubilizing agents including surfactants such as polysorbates, cyclodextrin, and cyclodextrin derivatives. (See paragraph [p0052].) While the prior art does not specifically teach tartarate is a stabilizer, the election of tartaric acid and the instant specification is evidenced that tartarate is a stabilizer. Chandrashekhar teaches suitable solvents include water, ethanol. (See paragraph 0055].) The teaching of water encompasses water for injection. Furthermore, Chandrashekhar teaches the formulation can be contained in an infusion bag. (See paragraph [0064].) Lastly, Chandrashekhar teaches the formulation may contain anti-oxidants and preservatives such as butylated hydroxyanisole (BHA), butylated hydroxyl toluene (BHT), citric acid, tocopherol, sorbic acid, monothioglycerol, ascorbic acid, boric acid, propyl gallate, aminoacids and mixtures thereof. (See paragraph [0056].)
Chandrashekhar does not teach the claimed the pH of about 2 to about 6 claimed. However, the pH range of 4-12 of Chandrashekhar touch the claimed concentration of netupitant and palonosetron and the claimed pH. Chandrashekhar does not disclose the exact claimed values, but does overlap: in such instances even, a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003). Moreover, Chandrashekhar does not teach netupitant and palonosetron as the sole active ingredients.
Renzo teaches efficacy and safety of multiple doses of NEPA without dexamethasone in preventing nausea and vomiting induced by multiple-day and high-dose chemotherapy in patients with non-Hodgkin’s lymphoma undergoing autologous hematopoietic stem cell transplantation in a phase IIa, multicenter study. (See Title.) Renzo also demonstrated that multiple alternate dosing of NEPA without the addition of dexamethasone is highly effective for preventing nausea and vomiting in this difficult setting, with a good tolerability profile. (See Abstract.) Renzo further teaches the administration of NEPA with an every other-day schedule demonstrated an excellent CINV control reaching a CR rate of 87.1% in the overall phase, defined as no emetic episodes and no rescue therapy. NEPA-based prophylaxis resulted not only very effective in the prevention of emesis but also quite efficient in controlling nausea. In comparison, the results obtained in our study are highly relevant being more effective and achieved without the use of HD dexamethasone. (See last paragraph of the right column of page 2117 bridging first paragraph of the left column of page 2118.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the composition of example 5 by replacing aprepitant with netupitant, replacing the sodium acetate with tartarate (salt of tartaric acid), and BHT with monthioglycerol with the exclusion of dexamethasone to give Applicant’s claimed invention. The motivation to do so is because Chandrashekhar teaches the pH ranges from 4 to 12, aprepitant can be replaced with Netupitant as an alternative NK1 receptor antagonist, sodium acetate with tartarate as an alternative buffering agent, and BHT and monothioglycerol as an alternative antioxidant, and also because Renzo the results obtained in our study for NEPA therapy (netuipitant and palonosetron) are highly relevant being more effective and achieved without the use of HD dexamethasone. One would reasonably expect the modified parenteral formulation to be effective for treating chemotherapy-induced nausea and vomiting with success with the absence or exclusion of dexamethasone. The replacement of aprepitant with netupitant with palonosetron renders the composition to have only two active ingredients.
Accordingly, the solution has netupitant N-oxide content of less than about 0.5% w/w with respect to total amount of netupitant in the solution after storage for 2 months at 25°C and 60% relative humidity according to claim 9 and the solution is physically stable and does not precipitate upon storage for at least 2 months at 25°C and 60% relative humidity according to claim 17. These limitations are the properties or functions of the liquid parenteral formulation. Therefore, since the claimed and prior art products are identical or substantially identical in structure or composition, the claimed properties or functions are necessarily present. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977).
Applicant argues that the inventors of the present application have surprisingly found that a narrow pH range of 2-6 holds paramount importance in ensuring the physical stability of an injectable netupitant solution. A pH range of 2-6, as required in claims 1, 12 and 19, is crucial for maintaining a stable solution of netupitant suitable for intravenous administration. This significance is not evident from Chandrashekhar or Renzo, nor can it be derived from the teachings of Chandrasekhar or Renzo, as explained in detail below. In fact, all parenteral solutions disclosed in Chandrasekhar have a pH of 7-9 and Renzo uses oral hard capsule formulations. Stable solutions are especially desirable for injectable compositions, particularly for intravenous administration: Injectable solutions are those products in which the drug, any added excipients, and any added co- solvents all truly dissolve in the vehicle (usually water). This type of presentation is the most common of the injectable drug products, and these types of products have the potential to be injected by any route of administration into the body. Parenteral suspensions and emulsions ... are extremely complex and difficult to formulate. Pg. 5, Chapter 13, Introduction to Biomanufacturing by The Northeast Biomanufacturing Center and Collaborative (https://biomanufacturing.org/uploads/files/412281068225186100-chapter-13.pdf). The difficulty and complexity in preparing parenteral emulsions or suspensions includes the need for several ingredients to obtain a stable emulsion or suspension, achieving desired bioavailability, and carefully controlling particle size of ingredients to avoid physiological complications upon parenteral administration. Stable solutions containing netupitant are difficult to develop and challenging to manufacture because netupitant is highly insoluble in aqueous environment. To overcome these challenges, a pro- drug of netupitant, i.e., fosnetupitant, has been developed to improve the solubility and obtain a viable stable liquid formulation of fosnetupitant suitable for parenteral administration. Netupitant demonstrates low solubility in aqueous environments, and there are currently no intravenous formulations of netupitant available in the market that are stable solutions. There exists a need for developing stable intravenous solution formulation of netupitant, alone or in combination with palonosetron, which are safe, therapeutically effective, and exhibit prolonged physical and chemical stability without any significant loss of potency. The present invention provides such a stable netupitant solution as claimed.
In response, Applicant’s argument is not persuasive. Applicant may well put the emphasis on the claimed narrow pH range. However, The Examiner notes that Chandrashekhar does disclose a broader overlapping range of pH (4-12) and ingredient concentrations. Slight difference in ranges is often considered obvious modifications unless supported by unexpected results. Applicant has not provided evidence of unexpected results tied to that specific narrow range of pH and the specific ingredients used at specific concentrations in the pharmaceutical formulation/solution. Moreover, Applicant citation of Pg. 5, Chapter 13, Introduction to Biomanufacturing by The Northeast Biomanufacturing Center and Collaborative cannot be commented on because such a reference is not cited in an IDS. Even assuming said reference is considered, the Examiner clarifies that difficulty in making parenteral formulation alone does not confer patentability. The inventive step requires showing how this narrow range with the specific ingredients and specific concentrations commensurate in scope with the claim unexpectedly solves the challenges beyond what the prior art suggests.
Applicant argues the prior art (Chandrashekhar) is contradictory, claiming instability or incompatibility of certain combinations or ingredients, while also claiming to have created a stable composition. Applicant also suggests this undermines the reliability of the teaching.
In response, Applicant’s argument is not persuasive. While isolated contradictions may appear, the overall teaching still provides guidance. A person of ordinary skill in the art can interpret and extract relevant disclosures. Thus, unless specific technical evidence shows the claimed invention achieves unexpected stability beyond Chandrashekhar suggests, the prior art remains a reasonable foundation for obviousness.
The Applicant’s argument is essentially saying that their claimed stable solution does not involve dexamethasone and that one skilled in the art wouldn’t expect all these NK antagonists (like netupitant) to behave similarly in stable storage. Applicant is invoking case law suggesting that the prior art related to different conditions or combinations wouldn’t be pertinent to their claimed invention.
In response, Applicant’s argument is not persuasive. Specifically, Chandrashekhar broadly teaches NK1 antagonists and excipients that overlap with the claimed ingredient and concentrations and conditions. Even without dexamethasone, the known properties of these antagonists and overlapping ranges would suggest that a skilled person would at least consider adapting these combinations. Thus, the prior art is still “reasonably pertinent” because it addresses similar technical challenges. Furthermore, Renzo directly teaches that effective stable formulation of netupitant and palonosetron do not require dexamethasone. This demonstrates that a person of ordinary skill in the art would have been motivated to consider stable NK-1 receptor antagonist formulations-like netupitant and palonosetron-even in the absence of dexamethasone. Thus, both Chandrashekhar and Renzo provide pertinent teachings that would lead a skilled artisan to expect workable solutions of the claimed type.
The Applicant’s argument boils down to two points. First, Applicant say the Examiner relies on an emulsion example from Chandrashekhar, while their claim is to a solution. They argue a skilled person wouldn’t substitute ingredients from that emulsion example to arrive at a stable solution. Second, Applicant claim Chandrashekhar does not explicitly teach stable solutions of netupitant, especially at the narrow pH range claimed.
In response, Applicant’s argument is not persuasive. Chandrashekhar clearly discloses the parenteral formulation is a stable formulation. (See paragraph [0035].) The solution is suitable for intravenous administration. Moreover, Chandrashekhar teaches the pH ranges from 4 to 12. (See claim 12.) Chandrashekhar teaches the concentration of Netupitant ranges from about 0.5 mg/ml to 100 mg/ml and the concentration of Palonosetron ranges from about 0.0005 mg/ml to 5 mg/ml. (See paragraph 0063].) The formulations can be administered as a ready to use solution; ready to dilute solution; lyophilized formulation; suspension, emulsion and the like. (See paragraph [0067].) A skilled person could adapt known ingredients and conditions toward a stable solution. Chandrashekhar also teaches solutions with overlapping pH ranges, and minor adjustments to pH or excipients would be routine optimization. Moreover, Applicants’ merely noting instability at a different pH (7-9) doesn’t automatically prove stability at their claimed pH range. Furthermore, it is widely known stability depends on the whole formulation-pH, ingredients, and ingredient’s concentrations. That’s why a person skilled in the art would be expected to adjust ingredients or conditions to achieve stability. In other words, swapping ingredients or narrowing pH is part of routine optimization.
The Applicant argues that their experiments on tables 15 and 24 show that netupitant solutions at pH of 2-6 exhibit stable physical properties, while solutions of pH 7-9 precipitate. They claim this is an unexpected result, providing the criticality of the 2-6 pH range.
In response, Applicant’s argument is not persuasive. While the Examiner acknowledges the data might show stability under certain conditions, the data are drawn to specific examples, using exact ingredients and concentrations. The claim in contrast, cover broad categories of stabilizers, solubilizers, and active ingredients (claim 12) without specifying exact formulations. Thus, the experimental examples, are not commensurate in scope with the claims. To show unexpected results across the full breadth of the claim-encompassing all stabilizers, and solubilizers, and actives in claim 12-Applicant would need to provide data or reasoning across the wider scope. The narrow examples cannot establish a broad, nonobvious trend unless they show it extends across the full breadth of what’s claimed.
The Applicant’s argument is that Renzo’s study focuses on an oral combination of netupitant and palonosetron, without dexamethasone, and shows efficacy in preventing nausea. Applicant argue that this demonstrates that stable, effective formulations, can be achieved without dexamethasone. In other words, Renzo’s teaching supports the idea that a skilled person using Applicant’s result could expect stable, effective solutions without needing dexamethasone.
In response, Applicant’s argument is not persuasive. Specifically, Renzo discusses efficacy, but clarify that the study uses a fixed oral dosage form and does not teach intravenous formulations or narrow pH ranges. The Examiner contends that Renzo’s teaching about efficacy does not address the specific stabilizer concentrations or pH range that the claim relies on. Again, the key point in Renzo’s study is the exclusion of dexamethasone. Renzo demonstrates a combination of netupitant and palonosetron, on its own, achieves effective nausea prevention. This supports that a person skilled in the art would find it obvious to adapt Chandrashekhar’s formulations by excluding dexamethasone. Thus, Renzo provides a clear rationale that dexamethasone is not essential, making the claimed formulation, without it, within ordinary skill. In other words, the teaching of efficacy without dexamethasone remove its necessity from the inventive step.
Modified and Revisited Rejection
Double Patenting
The non-statutory 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 non-statutory 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 non-statutory 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 non-statutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5-6, 8-19, and 21-23 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 12,097,197. Although the claims at issue are not identical, they are not patentably distinct from each other.
The U.S. patent claims teach a liquid pharmaceutical composition comprising:
(a) netupitant;
(b) at least one pharmaceutically acceptable stabilizer at a concentration of about 1.68 mg/mL to about 21.3 mg/mL selected from the group consisting of tromethamine, phosphoric acid, aspartic acid, tartaric acid, citric acid, maleic acid, ascorbic acid or mixtures thereof;
(c) at least one pharmaceutically acceptable solubilizer at a concentration of about 0.1 mg/mL to about 200 mg/mL selected from the group consisting of cyclodextrin, cyclodextrin derivatives, polysorbates, propylene glycol and mixtures thereof; and
(d) at least one pharmaceutically acceptable vehicle,
wherein netupitant is present at a concentration of about 0.5 mg/mL to about 20 mg/mL,
wherein the composition is in the form of a solution and has a pH of 2 to 6, and
wherein the solution is stable and suitable for parenteral administration. (See claim 1.)
Moreover, the U.S. patent claims teach a stable injectable pharmaceutical solution comprising:
(a) netupitant at a concentration of about 0.5 mg/mL to about 20 mg/mL and palonosetron hydrochloride at a concentration of about 0.001 mg/ml to about 0.1 mg/mL as the only active ingredients;
(b) at least one pharmaceutically acceptable stabilizer at a concentration ranging from about 1 mg/mL to about 22 mg/mL selected from the group consisting of tromethamine, phosphoric acid, aspartic acid, tartaric acid, citric acid, maleic acid, ascorbic acid and mixtures thereof; and
(c) at least one pharmaceutically acceptable solubilizer at a concentration of about 0.1 mg/mL to about 290 mg/mL selected from the group consisting of cyclodextrin, cyclodextrin derivative, polysorbate, propylene glycol and a mixture thereof; and
(d) at least one pharmaceutically acceptable vehicle,
wherein the solution has a pH ranging from 2 to 6, and wherein the solution is suitable for intravenous administration. The vehicle is selected from ethanol, water for injection and mixtures thereof, the solubilizer is present at a concentration of about 0.1 mg/mL to about 200 mg/mL, the solution is physically stable and does not precipitate upon storage for at least 2 months at 25° C. and 60% relative humidity, netupitant is present at a concentration of 1.975 mg/mL, and palonosetron hydrochloride is present at a concentration of 0.0028 mg/mL. (See claims 14-18.) The U.S. patent claims teach the solution has an osmolality value of about 100 mOsm to about 500 mOsm, the composition further comprises an antioxidant selected from the group consisting of butylated hydroxytoluene, monothioglycerol, sodium thiosulfate, sodium formaldehyde sulfoxylate and mixtures thereof, the vehicle is selected from ethanol, water for injection or mixtures thereof, and the solution has netupitant N-oxide content of less than about 0.5% w/w with respect to total amount of netupitant in the solution after storage for 2 months at 25° C. and 60% relative humidity. (See claims 2-5.) The U.S. patent claims also teach the solution is ready-to-use, the solution is ready-to-dilute, and the solubilizer is present at a concentration ranging from about 0.5 mg/mL to about 100 mg/mL. (See claims 6-8.)
The U.S. patent claims anticipate the instant claims.
Claims 1-3, 5-6, 8-19, and 21-23 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 12,370,190B2. Although the claims at issue are not identical, they are not patentably distinct from each other.
The U.S. patent claims teach a liquid pharmaceutical composition comprising:
(a) netupitant;
(b) at least one pharmaceutically acceptable stabilizer at a concentration of about 1.68 mg/mL to about 21.3 mg/mL selected from the group consisting of tromethamine, phosphoric acid, aspartic acid, tartaric acid, citric acid, maleic acid, ascorbic acid or mixtures thereof;
(c) at least one pharmaceutically acceptable solubilizer at a concentration of about 0.1 mg/mL to about 200 mg/mL selected from the group consisting of cyclodextrin, cyclodextrin derivatives, polysorbates, propylene glycol and mixtures thereof; and
(d) at least one pharmaceutically acceptable vehicle,
wherein netupitant is present at a concentration of about 0.5 mg/mL to about 20 mg/mL,
wherein the composition is in the form of a solution and has a pH of 2 to 6, and
wherein the solution is stable and suitable for parenteral administration. (See claim 1.)
Moreover, the U.S. patent claims teach a stable injectable pharmaceutical solution comprising:
(a) netupitant at a concentration of about 0.5 mg/mL to about 20 mg/mL and palonosetron hydrochloride at a concentration of about 0.001 mg/ml to about 0.1 mg/mL as the only active ingredients;
(b) at least one pharmaceutically acceptable stabilizer at a concentration ranging from about 1 mg/mL to about 22 mg/mL selected from the group consisting of tromethamine, phosphoric acid, aspartic acid, tartaric acid, citric acid, maleic acid, ascorbic acid and mixtures thereof; and
(c) at least one pharmaceutically acceptable solubilizer at a concentration of about 0.1 mg/mL to about 290 mg/mL selected from the group consisting of cyclodextrin, cyclodextrin derivative, polysorbate, propylene glycol and a mixture thereof; and
(d) at least one pharmaceutically acceptable vehicle,
wherein the solution has a pH ranging from 2 to 6, and wherein the solution is suitable for intravenous administration. The vehicle is selected from ethanol, water for injection and mixtures thereof, the solubilizer is present at a concentration of about 0.1 mg/mL to about 200 mg/mL, the solution is physically stable and does not precipitate upon storage for at least 2 months at 25° C. and 60% relative humidity, netupitant is present at a concentration of 1.975 mg/mL, and palonosetron hydrochloride is present at a concentration of 0.0028 mg/mL. (See claims 13-18.)
The U.S. patent claims teach the solution has an osmolality value of about 100 mOsm to about 500 mOsm, the composition further comprises an antioxidant selected from the group consisting of butylated hydroxytoluene, monothioglycerol, sodium thiosulfate, sodium formaldehyde sulfoxylate and mixtures thereof, the vehicle is selected from ethanol, water for injection or mixtures thereof, and the solution has netupitant N-oxide content of less than about 0.5% w/w with respect to total amount of netupitant in the solution after storage for 2 months at 25° C. and 60% relative humidity. (See claims 2-7.)
The U.S. patent claims also teach the solution is ready-to-use, the solution is ready-to-dilute, and the solubilizer is present at a concentration ranging from about 0.5 mg/mL to about 100 mg/mL. (See claims 8-9.)
The U.S. patent claims anticipate the instant claims.
The Applicant’s request that these nonstatutory double patenting rejection be held in abeyance is acknowledged. The nonstatutory double patenting rejections will remain in abeyance pending final determination of allowable claims. Once allowable claims are identified, suitable terminal disclaimers will be required to overcome these rejections.
Conclusion
Claims 1-3, 5-6, and 8-20 are not allowed.
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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/JEAN P CORNET/Primary Examiner, Art Unit 1628