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 .
Claims
The amendments received on July 1, 2026, have been entered. Claims 6, 10, 15, and 19 are pending and are examined in this Office Action.
Specification
The abstract of the disclosure is objected to because it is not descriptive enough of Applicant’s claimed invention. Abstracts should be 50-150 words in length, and for the currently claimed invention, the abstract should mention stability under refrigeration for at least 106 months. A corrected abstract of the disclosure is requested and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claim 15 is objected to because of the following informalities: “about 0.009 wt.% benzalkonium chloride” is recited twice. Appropriate correction is requested.
Claim Rejections - 35 USC § 112
Indefiniteness
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 6, 10, 15, and 19 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.
Each of these claims requires a solution with “about” 0.9 wt.% saline, “about” 0.009 wt.% or 0.009 vol.% benzalkonium chloride, and a pH range of “about” X to “about 4.5” and each requires an A280 absorbance of “about” 350-375 mg/mL. The use of the term “about” renders the claims indefinite because one of skill in the art would not know what concentration of saline or benzalkonium chloride is required, which pH is required, and which absorbance is required.
In the online Merriam-Webster dictionary, there is the following definition for “about”: a) reasonably close to, b) almost, c) on the verge of. ("About." Merriam-Webster.com. Merriam-Webster, n.d. Web. 13 Apr. 2018.).
A survey of US Patent applications shows a wide range of definitions for “about”. For example, in US 2018/0094234, page 14, ¶ 94: “Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects”.
US 2018/0028512, in ¶ 61: “The word “about” when immediately preceding a numerical value means a range of plus or minus 10% of that value … … unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values such as “about 49, about 50, about 55, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequence values, e.g., more than 49.5 to less than 52.5.”
US 2017/0367383, in ¶ 142: “As used herein, the terms “about” or “approximately” mean within an acceptable range for the particular parameter specified as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determine, e.g., the limitations of the sample preparation and measurement systems. Examples of such limitations include preparing the sample in a wet versus a dry environment, different instruments, variations in sample height, and differing requirements in signal-to-noise ratios. For example, “about” can mean greater or lesser than the value or range of values stated by 1/10 of the stated values, but is not intended to limit any value or range of values to only this broader definition. For instance a concentration value of about 30% means a concentration between 27% and 33%. Each value or range of values preceded by the term “about” is also intended to encompass the aspect of the stated absolute value or range of values. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.”
US 2023/0284585 A1, in ¶ 51, states the “term “about”, as used herein when referring to a measurable value such as a dosage or time period and the like, is meant to encompass variations of +/- 20%, +/- 10%, +/- 5%, +/- 1%, +/- 0.5%, or even +/- 0.1% of the specified amount”.
This demonstrates that there are a wide variety of standards for the meaning of the word “about”, from +/- 0.1% up to within an order of magnitude or +/- 20%, and also depending on the manner in which the measurements are made. For this reason, it is completely unclear what the metes and bound are for the required concentrations of saline or benzalkonium chloride, the required pH, and the required absorbance at A280 nm.
Lack of Scope of Enablement
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 6 and 19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a formulation of Crotoxin exhibiting stability comprising about 0.9 wt.% saline, 0.009 wt.% or 0.009 vol.% benzalkonium chloride, and a pH of 3.0-4.5, wherein the formulation is acidified using HCL, wherein the concentration as measured at A280 nm absorbance comprises 350-375 mg/mL after 106 months of storage at 2-10 oC, the specification does not reasonably provide enablement for such a formulation with a pH of about 1.5 – about 4.5. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The claims are directed to a formulation of Crotoxin exhibiting stability comprising with about 0.9 wt.% saline, about 0.009 wt.% or 0.009 vol.% benzalkonium chloride, and a pH range of about 1.5 to about 4.5, wherein the formulation is acidified using HCl, wherein the concentration as measured at A280 absorbance comprises about 350-375 mg/mL after 106 months storage at about 2-10 oC.
Applicant teaches that “according to one embodiment of the invention, Crotoxin was found to be stable in a saline solution for long periods even at an acid pH of less than 2.0, when the pH was lowered using Hydrochloric acid (HCl)” (Spec 4 ¶ 16). Applicant teaches that “according to one embodiment of the invention, it was found that Crotoxin could remain active when stored for long periods at a pH of 1.5 in a simple solution of 0.9% saline using HCl to power the pH” (Id.). It is unclear if this is prophetic or if these embodiments were actually reduced to practice because no working examples are provided with data to demonstrate these embodiments. In addition, it is unclear what is meant by “long periods”.
Applicant teaches “a reduction in the absorbance levels of the protein at 280 nm occurred when Crotoxin is in low pH solutions” (Spec 5 ¶ 16). Applicant teaches that the subunits of Crotoxin dissociate at a pH of less than 2.5 but this depends on the solution in which it is stored (Id. ¶ 17). Applicant teaches that “the lower pH solution retained its potency specification for over 24 months” (Id. 6 ¶ 19).
Applicant teaches “when stored refrigerated (1-10 oC) the potency of Crotoxin has been maintained for over 10 years formulated as ready-to-use in 0.9 wt.% saline at a pH of 3.0-4.0, using HCl for acidification, and benzalkonium 0.009chloride (approximating to 0.009 %)” (Spec 6 ¶ 20).
Applicant does not teach any formulation at a pH lower than 3.36 that is shown to exhibit stability for over 106 months in storage at 2-10 oC.
Applicant teaches a stable formulation of Crotoxin with 0.0088% - 0.0098% benzalkonium chloride in a 0.9% saline solution at pH 3.36 – 4.5 (Spec 7-8 Table 1). The working example shows a retention of absorbance at A280 nm between 350-374 mg/mL for a solution that began with an absorbance of 403 mg/mL (Id.).
Given the unpredictability around the stability of Crotoxin at lower pH, and the lack of any working examples at a pH lower than 3.36, it would require undue experimentation to determine how low a pH could be reduced to and remain stable for 106 months. Given Applicant’s own admitted state of the art, it would seem the solution would not be stable at pH 1.5 for 106 months.
Inadequate Written Description
Claims 6 and 19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a formulation of Crotoxin exhibiting stability comprising about 0.9 wt.% saline, 0.009 wt.% or 0.009 vol.% benzalkonium chloride, and a pH of 3.0-4.5, wherein the formulation is acidified using HCL, wherein the concentration as measured at A280 nm absorbance comprises 350-375 mg/mL after 106 months of storage at 2-10 oC, the specification does not reasonably provide enablement for such a formulation with a pH of about 1.5 – about 4.5. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The claims are directed to a formulation of Crotoxin exhibiting stability comprising with about 0.9 wt.% saline, about 0.009 wt.% or 0.009 vol.% benzalkonium chloride, and a pH range of about 1.5 to about 4.5, wherein the formulation is acidified using HCl, wherein the concentration as measured at A280 absorbance comprises about 350-375 mg/mL after 106 months storage at about 2-10 oC.
Applicant describes “one embodiment of the invention, Crotoxin was found to be stable in a saline solution for long periods even at an acid pH of less than 2.0, when the pH was lowered using Hydrochloric acid (HCl)” (Spec 4 ¶ 16). Applicant describes “one embodiment of the invention, it was found that Crotoxin could remain active when stored for long periods at a pH of 1.5 in a simple solution of 0.9% saline using HCl to power the pH” (Id.). It is unclear if this is prophetic or if these embodiments were actually reduced to practice because no working examples are provided with data to demonstrate these embodiments. In addition, it is unclear what is meant by “long periods”.
Applicant describes “a reduction in the absorbance levels of the protein at 280 nm occurred when Crotoxin is in low pH solutions” (Spec 5 ¶ 16). Applicant descrbes the subunits of Crotoxin dissociate at a pH of less than 2.5 but this depends on the solution in which it is stored (Id. ¶ 17). Applicant describes “the lower pH solution retained its potency specification for over 24 months” (Id. 6 ¶ 19).
Applicant describes “when stored refrigerated (1-10 oC) the potency of Crotoxin has been maintained for over 10 years formulated as ready-to-use in 0.9 wt.% saline at a pH of 3.0-4.0, using HCl for acidification, and benzalkonium 0.009chloride (approximating to 0.009 %)” (Spec 6 ¶ 20).
Applicant does not describe any formulation at a pH lower than 3.36 that is shown to exhibit stability for over 106 months in storage at 2-10 oC.
Applicant describes a stable formulation of Crotoxin with 0.0088% - 0.0098% benzalkonium chloride in a 0.9% saline solution at pH 3.36 – 4.5 (Spec 7-8 Table 1). This reduction to practice shows a retention of absorbance at A280 nm between 350-374 mg/mL for a solution that began with an absorbance of 403 mg/mL (Id.).
Given the unpredictability around the stability of Crotoxin at lower pH, and the lack of any reduction to practice at a pH lower than 3.36, it does not appear that Applicant was in possession of the claimed formulation across the full breadth of the current claims.
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 of this title, 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.
Claims 6, 10, 15, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Reid et al. (US Pre-Grant Publication US 2006/0034823 A1 published on Feb. 16, 2006) in view of Reid P. F. (US Pre-Grant Publication US 2019/0336572 A1 published on Nov. 7, 2019, referred to hereafter as “Reid2”), and further in view of Fenton et al. (The Journal of Biological Chemistry (1977) Vol. 252; pp. 3587-3598).
The claims are directed to a formulation of Crotoxin exhibiting stability comprising with about 0.9 wt.% saline, about 0.009 wt.% or 0.009 vol.% benzalkonium chloride, and a pH range of about 1.5 to about 4.5, wherein the formulation is acidified using HCl, wherein the concentration as measured at A280 absorbance comprises about 350-375 mg/mL after 106 months storage at about 2-10 oC.
Reid teaches a composition comprising crotoxin in a saline suspension buffer at 0.9% sterile saline (Reid 4 ¶ 47). Reid teaches monitoring at 280 nm for peaks after column chromatography (Id.). Reid teaches a standard formulation for crotoxin that comprises 500-2000 mg/mL and can be as dilute as 90 mg/mL; also comprising 0.9% chloride and 0.001% benzalkonium chloride (Reid 4 ¶ 42). The Examiner interprets 0.001% benzalkonium chloride as “about” 0.0009% benzalkonium chloride.
Reid claims a composition comprising Crotoxin at a concentration between 6 mg and 1 mg per gram of base, and this converts to 6-1000 mg/mL if the base is an aqueous solution (claim 5). Reid additionally claims a composition comprising crotoxin at 100-200 mg/gram of base (claim 6).
The Examiner interprets 500-2000 mg/mL and 100-200 mg/gram and 6-1000 mg/mL to each be “about” 350-375 mg/mL given that there is no definition in the instant specification for the term “about” and the examples of definitions included in the indefiniteness rejection include “about” encompassing values within an order of magnitude.
Reid does not teach a formulation of crotoxin having benzalkonium chloride at exactly 0.009%, nor having a pH of 1.5-4.5 adjusted with HCl, nor having a concentration in the exact range of 350-375 mg/mL as measured by absorbance at A280 nm after having been stored at 2-10 oC for 106 months.
Reid2 claims a composition comprising cobra venom with a shelf life of protein stability under refrigeration of about 10 years (Reid2 claim 15). Reid2 teaches such a composition in a 0.9% saline solution comprising 0.007% BZK (benzalkonium chloride) (Id. 4, Example 1 ¶ 32). Reid2 teaches a pH range from 4.0-7.0 for different formulations of this cobra venom (Id. Example 3 ¶ 36).
Using HCl to adjust the pH of solutions was standard in the art, and a refrigerated temperature of 4 oC is standard in the art, as taught by Fenton (Fenton 3589, Figure 1; and paragraph bridging pp. 3590-3591; and left column on page 3591).
At the time the instant application was filed, it would have been obvious and within the scope of one of ordinary skill in the art to modify the composition taught by Reid to adjust the pH to 4.0 as taught by Reid2 using HCl as taught by Fenton. The precise pH and precise concentrations of saline, benzalkonium chloride, and crotoxin are all within the ranges taught in the prior art, and in the absence of any showing of criticality or unexpected results, they are obvious variations within the parameters taught in the prior art. Using 4 oC as the temperature for refrigeration is standard in the art, as taught by Fenton, and given that Reid2 teaching long term shelf life “under refrigeration”, using 4 oC as the temperature for storage would have been obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory obviousness-type 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); and 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 a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 6, 10, 15, and 19 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-5, 7-9, 11-14m 16-18, 20, and 21 of copending Application No. 18910526. Although the conflicting claims are not identical, they are not patentably distinct from each other for the following reasons.
The claims of the copending application teach and/or suggest the claimed formulation of Crotoxin exhibiting stability comprising a saline solution, benzalkonium chloride and a pH of about 1.5 to about 4.5, wherein the formulation is acidified using HCl. Thus, the teachings anticipate the claimed invention.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Summary
No claim is allowed
Examiner’s Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHY KINGDON whose telephone number is (571)272-8784. The examiner can normally be reached M-F 9:00 - 5:30 EST.
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CATHY KINGDON
Primary Examiner
Art Unit 1663
/CATHY KINGDON/Primary Examiner, Art Unit 1663
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