DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application claims priority to provisional application 63/427,226 filed on 22 November 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 17 May 2024 is acknowledged and considered.
Claim Rejections - 35 USC § 112 (b)
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 1-8 and 12-15 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.
Claims 1 and 15 recite “… water at a level between 2.0% and 5.0%” wherein the unit of concentration is not defined. It is unclear whether the % in claims 1 or 15 is % w/w or some other %. Applicant may overcome the rejection by adding “w/w”.
Claim 15 recites “… and one or more antioxidants at …” and proceeds to state the two antioxidants at a certain amount. It is unclear if both the stated antioxidants are required in the stated amounts or if just one is required. Claims 2-8 and 12-14, which depend from claim 1, incorporate the indefinite subject matter of claim 1 and fail to cure the deficiency of claim 1. Appropriate correction is requested.
Claim Rejections - 35 USC § 112 (d)
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.
Claims 5-11 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.
Claims 5, 9 and 11, dependent on claim 1, recite “…dehydrated alcohol.” For example, claim 5 recites 60% w/w to 95% w/w dehydrated alcohol. Claim 1 recites “ethanol at about 2% w/w to 50% w/w” which is a narrower in scope to the limitation in the dependent claims regarding the permissible ethanol and a different scope regarding the permissible percentage thereof. Claims 6-8 and 10, depend on claim 3, which depends from claim 1, and have the same “…dehydrated alcohol” limitation. Claim 3, which is dependent on claim 1, incorporates by reference the limitation “ethanol” as the solution in which cyclophosphamide will be formulated in. The specification does not define “dehydrated alcohol” as being “anhydrous ethanol”, thus “dehydrated alcohol” is given its broadest reasonable interpretation (MPEP §2111) which can broadly be understood to be any type of alcohol, including ethanol, which has a low water content. Therefore, the “dehydrated alcohol” limitations in the instant claims broaden and do not further limit the “ethanol” limitation and claims 5-11 are in improper dependent form because they fail to include all limitations from the claim from which they depend (MPEP §608.01(n)(III)).
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.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-15 are rejected under 35 U.S.C. 103 as being unpatentable over Shaik (US Patent No. 11,382,923).
Shaik teaches stable liquid formulations of cyclophosphamide can be used for parenteral administration as ready-to-use or ready-to-dilute for treating various cancer disorders (Abstract and ¶ [0002]). There are two forms of solid cyclophosphamide, namely the monohydrate and anhydrous form. The monohydrate is preferred for pharmaceutical processing because the anhydrous form is unstable and readily picks up water to form the monohydrate (column 2, lines 4-10). Example 4 shows a manufacturing process that dissolves cyclophosphamide monohydrate (500mg) in anhydrous ethanol until the solution is homogenous, subsequently brought to the desired volume with anhydrous ethanol (1mL), and charged with molecular sieves (1 part cyclophosphamide bulk solution to 0.5 parts molecular sieves) and incubated at 2-8°C and analyzed at several time points. The initial water content shows 3.54% and is reduced over time in the presence of molecular sieves (column 22, Example 4, Table 5). Shaik also teaches that antioxidants may be added as excipients such as butylated hydroxytoluene, monothioglycerol, ascorbic acid, thymol, etc. and can make up 0.01% to about 10% w/w of the formulation (column 16, lines 12-21).
Shaik does not teach specific formulations containing antioxidants nor does it teach a range of concentrations between 2% w/w to 40% w/w of cyclophosphamide monohydrate in anhydrous ethanol.
Shaik is considered analogous art to the claimed invention because it is in the same field of formulating stable liquid compositions of cyclophosphamide where in the water concentration is less <5%. Therefore, it would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) before the effective filing date of the claimed invention, to follow the teachings of Shaik to formulate a stable liquid composition of cyclophosphamide which contains less than 5% moisture content (column 6, lines 37-40). A PHOSITA would have been motivated by these teachings to formulate stable liquid compositions of cyclophosphamide, with minimal water content, because of the issues associated with reconstitution of lyophilized cyclophosphamide, including using water as the solvent and immediate use after reconstitution (column 3, lines 6-12, 50-55).
Regarding claims 1-2 and 5, Shaik teaches Example 4, wherein cyclophosphamide monohydrate (500mg) is dissolved in anhydrous ethanol until the solution is homogenous and subsequently brought to the desired volume with anhydrous ethanol (1mL). Other embodiments of the invention are taught, wherein the pharmaceutically effective concentration of cyclophosphamide is in the range of 0.1 g/mL – 5g/mL (column 17, lines 53-55), the water content of the cyclophosphamide is <5% (column 10, lines 32-35), and the solvent anhydrous ethanol and can be present in a concentration range of 10 to 100% by weight of the composition (column 13, lines 41-56). While the exact w/w% of cyclophosphamide cannot be resolved, a PHOSITA would understand that the amounts taught likely overlap with those instantly claimed and otherwise overlap with the other embodiments taught or would be attained under routine optimization. The prior art provides workable ranges of identical components and selecting the instantly claimed concentration of cyclophosphamide, wherein the water content is <5%, and proper volume of anhydrous ethanol to dissolve the cyclophosphamide would have been routine to a PHOSITA and therefore prima facie obvious (MPEP §2144.05(II)(A)).
Regarding claims 3-4, Shaik teaches antioxidants can be included in the liquid formulation of cyclophosphamide which include butylated hydroxytoluene and monothioglycerol (column 16, lines 12-21). Incorporating an antioxidant such as butylated hydroxytoluene, monothioglycerol, or a combination thereof, would have been routine to a PHOSITA (MPEP §2144.05(II)(A)).
Regarding claims 6-7, Shaik teaches that the liquid formulations of the cyclophosphamide compositions can include antioxidants such as butylated hydroxytoluene or monothioglycerol, and can be present in the range of about 0.01% w/w to about 10% w/w of the formulation (column 16, lines 12-21). These ranges overlap with the ranges instantly claimed and would have been prima facie obvious to a PHOSITA to choose these antioxidants within the concentration range instantly claimed (MPEP §2144.05(I)).
Regarding claim 8, Shaik teaches that antioxidants like monothioglycerol and butylated hydroxytoluene can be added as a combination at a concentration range of 0.01% w/w to about 10% w/w (column 16, lines 12-21). These concentration ranges overlap with the concentrations instantly claimed and the addition of the combination of these antioxidants would have been obvious for a PHOSITA to combine these antioxidants as they are taught to be useful for the same purpose as antioxidants (MPEP §2144.05(I) & §2144.06(I)).
Regarding claims 9-11, Shaik teaches stable liquid formulations of cyclophosphamide can be made containing water content <5% (column 10, lines 32-35). The ranges of cyclophosphamide, water content, anhydrous ethanol, and monothioglycerol overlap with the ranges instantly claimed and would have been routine for a PHOSITA to optimize (MPEP §2144.05(I)&(II)).
Regarding claims 12-13, Shaik teaches glycols like propylene glycol and polyethylene glycol are suitable excipients as non-aqueous solvents of cyclophosphamide liquid formulations (column 13, lines 41-46). Substituting known equivalents of non-aqueous solvents would have been prima facie obvious to a PHOSITA (MPEP §2144.06(II)).
Regarding claim 14, Shaik teaches that chloride ion sources in the cyclophosphamide liquid formulation can minimize attack on the carbons containing the chlorine atom. Suitable chloride ion sources to stabilize the formulation are sodium chloride, potassium chloride, hydrochloric acid, etc. The chloride ion source may be present in the range of 0.01% to about 15% w/w of the formulation (column 14, lines 63-67; column 15, lines 1-5). Instant claim 14, uses the word stabilizer which Shaik teaches to be a chloride ion source; therefore, is rendered prima facie obvious.
Regarding claim 15, Shaik teaches embodiments of the invention wherein the pharmaceutically effective concentration of cyclophosphamide is in the range of 0.1 g/mL – 5g/mL (column 17, lines 53-55), the water content of the cyclophosphamide is <5% (column 10, lines 32-35), and the solvent anhydrous ethanol can be present in a concentration range of 10 to 100% by weight of the composition (column 13, lines 41-56). Furthermore, Shaik teaches that the liquid formulations of the cyclophosphamide compositions can include antioxidants such as butylated hydroxytoluene, monothioglycerol, and combinations thereof, and can be present in the range of about 0.01% w/w to about 10% w/w of the formulation (column 16, lines 12-21). These concentration ranges overlap with the concentrations instantly claimed and the addition of the combination of these antioxidants would have been prima facie obvious to a PHOSITA to combine these antioxidants as they are taught to be useful for the same purpose as antioxidants (MPEP §2144.05(I) & §2144.06(I)).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAHIL CHANDER AGGARWAL whose telephone number is (571)272-7755. The examiner can normally be reached 7am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAHIL CHANDER AGGARWAL/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
