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 .
Claim Status
Claims 1-20 are pending and presently considered.
Election/Restriction
Applicant’s election without traverse of a species in the reply filed on 5/11/2026 is acknowledged.
The species is understood to be disclosed at Example 12 (see, e.g., Specification filed 6/20/2023 at ¶¶[0146]-[0148]), which follows the general procedure of Example 1 (see, e.g., Specification filed 6/20/2023 at ¶¶[0075]-[0086]), which has Steps (a)-(f) (see, e.g., Reply filed 5/11/2026 at 1-4).
Step (a) (Preparation of Substrate Solution): Compound a361 (MW 1,299.71; CLogP 13.64, 11 amino acids, mixed with the organic solvent of tert-butyl alcohol (TBA) and water. The weight percentage of TBA based on the total weight of TBA and water is 90%, wherein the mixed solvent has a freezing point of about -7°C, and the substrate solution was prepared as 10% w/v (see, e.g., Reply filed 5/11/2026 at 1-2).
Step (b) (Freezing step): The cooling temperature in this step was -45°C. (see, e.g., Specification filed 6/20/2023 at ¶[0076]).
Step (c) - (Primary Drying (First Stage of Drying)): The pressure in this step was 150 mTorr (about 20 Pa), and the temperature was raised from -45°C to -25°C and kept at -25°C (see, e.g., Specification filed 6/20/2023 at ¶[0077]).
Step (d) - (Secondary Drying (Second Stage of Drying)): The pressure is the same as in Step (c). The temperature was raised from -25°C to 40°C and kept at 40°C (see, e.g., Specification filed 6/20/2023 at ¶[0078]).
Step (e) - (Pretreatment for Measurement of Residual Solvent Concentration): No step (e) identified in the response (see, e.g., Reply filed 5/11/2026 at 2).
Step (f) - (Measurement of Residual Solvent Concentration): The residual solvent concentration in the freeze-dried powder of Example 12 was determined to be 0.14 % (see, e.g., Specification filed 6/20/2023 at Table 3 at ¶[0147]).
The reply identifies that “Example 12 contains no separate “freezing step” distinct from the “pre-freezing step of Step (b)” (see, e.g., Reply filed 5/11/2026 at 2). Accordingly, any step occurring prior to the solution actually freezing is reasonably inferred to satisfy the requirement of a “pre-freezing” step.
Following extensive search and examination, the originally elected species has been deemed free of the prior art. This determination is premised upon the exact combination of steps, reagents, Compound a36, and residual solvent reported. Per MPEP § 803.02(III)
If the examiner determines that the elected species is allowable over the prior art, the examination of the Markush claim will be extended. If prior art is then found that anticipates or renders obvious the Markush claim with respect to a nonelected species, the Markush claim shall be rejected; claims to the nonelected species would still be held withdrawn from further consideration. The prior art search will not be extended unnecessarily to cover all nonelected species.
No species are presently recited within the pending claims; accordingly, Examination was extended to a non-elected species and subgenus of an API (“Active Principle Ingredient”) with 80% Tert-butanol with water, subjected to freeze-drying. Following extensive search and examination, the non-elected species was deemed anticipated and/or obvious in view of the prior art as applied below. Per MPEP § 803.02(III), claims directed to other nonelected species have been withdrawn.
Claims 1-20 are presently considered.
Priority
The priority claim to PCT/JP2021/047164 (filed 12/21/2021) is acknowledged.
Examiner notes that no certified translation of the Foreign Application JP2020-211922 (filed 12/22/2020) has been placed on record. If applicant wants the application to be accorded benefit of the non-English language application, a certified translation is required (see 35 U.S.C. 119(b)(3), 37 CFR 1.55(g)(1)-(4)). Applicant is advised that any showing of priority that relies on a non-English language application is prima facie insufficient if no certified translation of the application is on file. See 37 CFR 41.154(b).
Information Disclosure Statement
The IDS filed 5/11/2026 is acknowledged and presently considered.
Claim Interpretation
For purposes of examination, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
Claim 1 is representative of the pending claim scope and presently recites:
1. (Original) A medicine production method comprising the following steps:
(1) providing a mixed solution containing water, an organic solvent, and a substance to be freeze-dried; and
(2) subjecting the mixed solution to freeze-drying,
wherein a weight percentage of the organic solvent based on a total weight of water and the organic solvent in the step (1) is 68% by weight or more and 99% by weight or less.
Accordingly, the pending claims are directed to a method of freeze-drying any substance, wherein the mixture contains water, an organic solvent, and a substance to be freeze-dried, and wherein the solvent utilized is 68-99% organic solvent by percent weight.
Regarding the preamble phrase “medicine production method”, per MPEP § 2111.02, “where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation”. Here, the recitation of a “medicine” is reasonably inferred to require that the “substance to be freeze-dried” is suitable for use in medical or biomedical assays.
“Comprising” is an open-ended transitional term (see, e.g., MPEP § 2111.03(I)), wherein additional steps or components are not excluded. However, “‘[c]omprising’ is a term of art used in claim language which means that the named elements are essential” (see, e.g., id.; see also Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997)).
“Containing” is understood to be synonymous with “comprising” (see, e.g., MPEP § 2111.03(I)).
“Organic solvent” is functionally defined on record as any organic compound that has “a higher vapor pressure as compared with the vapor pressure of water and have a lower latent heat of sublimation as compared with the latent heat of sublimation of water” (see, e.g., Specification filed 6/20/2023 at ¶[0051]). It is unclear what organic solvents do or do not satisfy this functional limitation, and no structure function guidance is provided. However, the original disclosure identifies the following organic solvents explicitly: t-butanol, dimethyl sulfoxide, 1,4-dioxane, acetonitrile, acetic acid, cyclohexane, and dimethy 1 carbonate. Accordingly, the metes and bounds of “organic solvent” is unknown, but reasonably inferred to encompass at least the explicitly recited compounds in the Specification (see, e.g., Specification filed 6/20/2023 at ¶[0051]).
“Substance to be freeze-dried” is unlimited (see, e.g., Specification filed 6/20/2023 at ¶¶[0011]-[0016], [0056]). The phrase includes any biochemical compounds, including peptides.
“Pre-freezing step” (recited at claim 4) is not limited and is understood to be any step that occurs prior to the actual moment that the mixture is frozen (see, e.g., Specification filed 6/20/2023 at ¶¶[0059]-[0061]).
“Freeze-drying” is understood to be “a process of sublimating the solvent in a sample in a frozen state to remove the solvent” (see, e.g., Specification filed 6/20/2023 at ¶¶[0058]).
The wherein clause at claim 1 reciting
wherein a weight percentage of the organic solvent based on a total weight of water and the organic solvent in the step (1) is 68% by weight or more and 99% by weight or less;
is reasonably inferred to refer to the “mixed solution” at claim 1(1) prior to being freeze-dried.
At claim 15, the phrase “wherein a residual solvent concentration in a freeze-dried powder by the freeze-drying is 1.2% or less” is a recitation of an outcome Applicant desires to achieve, but does not recite additional “hand-of-man” steps or structural changes. Per MPEP § 2111.04(I), “Claim scope is not limited by claim language that . . . . does not require steps to be performed, or by claim language that does not limit a claim to a particular structure”, and further states that a “whereby clause” in a claim “is not given weight when it simply expresses the intended result of a process step positively recited”. Here, the “wherein” clause does not unambiguously correspond to a clear structure/function relationship in the original disclosure, and therefore is not reasonably deemed a functional limitation. Rather, the “wherein” clause is understood to merely recite an intended or expected result fully satisfied by the positively recited steps and/or structures set forth in the body of claim 1, from which claim 15 depends. Therefore, the “wherein” clause of claim 15 is understood to be a recitation of intended and expected results fully satisfied by any prior art method that satisfies the positively recited active method steps of instant claim 1. If Applicant disagrees, Applicant should identify what species within the scope of claim 15 are not enabled by the steps and structures set forth at claim 1.
“Room temperature” is “1-30°C” (see, e.g., Specification filed 6/20/2023 at ¶¶[0045]).
“Non-natural amino acid” is understood to be any amino acid other than the “natural amino acids” enumerated at page 7 (see, e.g., Specification filed 6/20/2023 at ¶¶[0016]).
Additional claim interpretations are discussed below.
Claim Objections
Claim 1 and 5 are objected to because of the following informalities:
At claim 1, the “wherein” clause at the last two lines are confusingly placed after Claim 1(2), but the “wherein” clause applies to the mixture of claim 1(1) prior to freezing. For clarification and to avoid confusion regarding potential timing issues (i.e., the solvent percentage presumably changes during the freeze-drying process), the “wherein” clause should be placed after claim 1(1) and prior to claim 1(2).
At claim 5, the phrase “step(2) comprising a drying step having a plurality of stages, which comprise a first stage and a second stage” appears redundant. Redundant and superfluous language should be removed to enhance claim clarity and avoid confusion. For example, the claim may be amended to recite “step (2) comprising a drying step .
Appropriate correction is required.
Claim Rejections
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 1-6 and 8-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the term “organic solvent”, which is given a functional definition (see, e.g., Specification filed 6/20/2023 at ¶[0051]). Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “organic solvent” in claim 1 is used by the claim to mean “an organic compound that has ‘a higher vapor pressure as compared with the vapor pressure of water and have a lower latent heat of sublimation as compared with the latent heat of sublimation of water’” (see, e.g., Specification filed 6/20/2023 at ¶[0051]), while the accepted meaning is simply “a carbon-based solvent”. The term is indefinite because, although the Specification provides a functional description of what Applicant hopes and desires for a compound to achieve, the specification does not actually disclose a meaningful structure/function relationship that provides unambiguous metes and bounds of what compounds do or do not infringe. MPEP § 2173.05(g) explains that functional language may render a claim indefinite when the functional language fails to provide a clear indication of the scope of the subject matter embraced by the claim. Notably, MPEP § 2173 identifies that the primary purpose of the requirement is to inform the public of the boundaries of what constitutes infringement of the patent, but here it is unclear what compounds do or do not infringe upon the scope of claim 1, because it is unclear what structures do or do not exhibit “a higher vapor pressure as compared with the vapor pressure of water and have a lower latent heat of sublimation as compared with the latent heat of sublimation of water” (see, e.g., Specification filed 6/20/2023 at ¶[0051]). Notably, the courts have stated that
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
Accordingly, because it is unclear what compounds do or do not satisfy the functionally defined term “organic solvent” at claim 1, an artisan would be unable to identify infringing from non-infringing compounds; therefore, claim 1 is rejected as indefinite. For purposes of applying prior art, the term “organic solvent” is understood to encompass at least t-butanol, dimethyl sulfoxide, 1,4-dioxane, acetonitrile, acetic acid, cyclohexane, and dimethy 1 carbonate (see, e.g., Specification filed 6/20/2023 at ¶[0051]).
Claim 15 recites the “wherein” clause “wherein a residual solvent concentration in a freeze-dried powder by the freeze-drying is 1.2% or less”, which is either
(i) a recitation of an intended and expected result, fully satisfied by the positively recited method steps set forth in the body of instant claim 1, from which claim 15 depends (see, e.g., MPEP § 2111.04(I), see claim interpretation section, above); or
(ii) a functional limitation that further limits the structures and/or hand-of-man steps performed relative to instant claim 1.
Notably, under interpretation (i), the “wherein” clause does not satisfy 35 USC § 112(d) because it has the same scope as instant claim 1. Alternatively, under interpretation (ii), the “wherein” clause does not satisfy 35 USC § 112(b) per MPEP § 2173.05(g), which explains that
[T]he use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite. In re Swinehart, 439 F.2d 210, 213 (CCPA 1971). For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. . .
Here, if the “wherein” clause is a functional limitation, it merely recites a description of a problem to be solved or a function or result to be achieved, but fails to provide a description of any structural limitations beyond those recited at claim 1, that are required to actually achieve the function or result. Accordingly, if the “wherein” clause is intended to be further limiting by reciting a functional limitation, then it is rejected as indefinite because the “wherein “clause fails to correspond to a structure/function relationship permitting artisans to identify structures required to achieve the function or result recited. For purposes of applying prior art, claim 15 is interpreted consistent with interpretation (i), above.
Claim 16 recites the limitation "the cooling temperature" at line 1. There is insufficient antecedent basis for this limitation in the claim.
Claims 2-6 and 8-20 depend directly or indirectly from an indefinite base claim and fail to reconcile the indefiniteness of the base claim. Accordingly, claims 2-6 and 8-20 are rejected as indefinite as depending upon an indefinite base claim.
Claims 1-6 and 8-20 are rejected.
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.
Claim 15 is 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.
Claim 15 depends from claim 1, and differs from claim 1 only by the recitation of a “wherein” clause that does not correspond to any structure/function relationship of record, and therefore the “wherein” clause is not reasonably understood to be a further limiting functional limitation (see discussion under 35 USC §112(b) regarding claim 15, incorporated herein; see also MPEP § 2111.04(I) and Claim Interpretation section set forth above, incorporated herein). Accordingly, claim 15 and claim 1 are understood to have the same exact claim scope, same structures, and same “hand-of-man” steps, and only differ because claim 15 explicitly recites an intended and expected outcome satisfied by all embodiments of claim 1 satisfying the positively recited active method steps within the body of claim 1. Accordingly, claim 15 is rejected under 35 USC § 112(d) for failing to further limit the subject matter of the claim upon which it depends. If Applicant disagrees, Applicant should explicitly identify a single embodiment of method that is within the scope of instant claim 1, but is excluded from the scope of instant claim 15 by failing to satisfy the “wherein” clause.
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 § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
[Prior Art Rejection 01]
Claims 1-2, 4-13, and 15 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being clearly anticipated by WO2017/149077A12 (Sept. 8, 2017) as evidenced by CAS Reg. No. 2130958-62-0 (attached as 6 pages, June 2, 2026), and as further evidenced by Vessot et al.3,
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
WO’077 pertains to Amanitin conjugates (see, e.g., WO’077 at title, abs, ¶[001]). Regarding the instant claims, WO’077 describes a method of producing a conjugate, wherein the intermediate is freeze-dried (see, e.g., WO’077 at ¶¶[00114], [00126]). Regarding instant claim 1, 1(1), and 1(2), WO’077 exemplifies a method wherein the intermediate cyclic peptide of “HDP 30.1895”4 (see WO’077 at ¶[00122], reproduced in part below):
PNG
media_image1.png
264
283
media_image1.png
Greyscale
(15.0 mg, 15.3 µM) was dissolved in 7 N methanolic NH3 solution (3.0 mL) and “stirred overnight” and then “the reaction was concentrated in vacuum” and then the concentrated solution was “suspended in 80% tert-butanol and lyophilized” (see, e.g., WO’077 at ¶¶[00114], [00122], [00126]), wherein 80% tert-butanol is understood to be “t-butanol/water 4:1” (see, e.g., WO’077 at ¶[00143], noting that product containing fractions evaporated and lyophilized from t-butanol/water 4:1 resulted in product). Accordingly, the prior art satisfies instant claim 1(1) and 1(2), because the prior art discloses a method wherein a mixed solution containing water, the organic solvent of t-butanol, and the cyclic peptide of “HDP 30.1895” (i.e., a “substance to be freeze-dried”) was provided (see, e.g., WO’077 at ¶¶[00114], [00126]), and this mixed solution was subsequently lyophilized (see, e.g., WO’077 at ¶¶[00114], [00122], [00126]). Regarding instant claim 1 and the “wherein” clause requiring that “a weight percentage of the organic solvent based on a total weight of water and the organic solvent in the step (1) is 68% by weight or more and 99% by weight or less”, the 80% tert-butanol utilized is understood to be “t-butanol/water 4:1” (see, e.g., WO’077 at ¶[00143]), which is understood to be approximately ~75.6 % wt/wt t-butanol5 (see, e.g., WO’077 at ¶¶[00114], [00122], [00126], [0143]). Regarding instant claim 2 and actively mixing the mixed solvent and the substance to be freeze-dried at claim 1 step(1), the mixed solvent containing water and the organic solvent, 80% tert-butanol, (see, e.g., WO’077 at ¶[00143]) was added to the concentrated solution, and “suspended in 80% tert-butanol and lyophilized” (see, e.g., WO’077 at ¶¶[00114], [00122], [00126]), wherein “suspended” is understood to necessarily and inherently involve some level of “mixing”. Regarding instant claim 4 and the method of claim 1(2) comprising a “pre-freezing step”, critically “pre-freezing step” is not limited and is understood to include any step that occurs prior to the actual moment that the mixture is frozen (see, e.g., Specification filed 6/20/2023 at ¶¶[0059]-[0061]). WO’077 teaches and discloses that the composition is lyophilized (see, e.g., WO’077 at ¶¶[00126], [0143]), and an artisan would readily appreciate that lyophilization necessarily and inherently involved a cooling step as evidenced by Vessot (see, e.g., Vessot at 377 at col I-II at § Introduction, explaining that lyophilization “is the process by which the solvent is removed from a frozen solution by sublimation”, wherein “The freeze-drying process may be divided into three steps: Freezing, primary drying (or sublimation), and secondary drying (or desorption)”). Accordingly, in view of the disclosure of WO’077 that lyophilization was used (see, e.g., WO’077 at ¶¶[00126], [0143]), and artisan would readily infer and at once envisage a pre-freezing step, wherein the composition is actually frozen in view of the art-recognized definition and meaning of “lyophilization”. Regarding instant claim 5 and the method of claim 1(2) comprising a drying step having a “first stage” and a “second stage”,
WO’077 teaches and discloses that the composition is lyophilized (see, e.g., WO’077 at ¶¶[00126], [0143]), and an artisan would readily appreciate that lyophilization necessarily and inherently involved a cooling step as evidenced by Vessot (see, e.g., Vessot at 377 at col I-II at § Introduction, explaining that lyophilization “is the process by which the solvent is removed from a frozen solution by sublimation”, wherein “The freeze-drying process may be divided into three steps: Freezing, primary drying (or sublimation), and secondary drying (or desorption)”). Accordingly, in view of the disclosure of WO’077 that lyophilization was used (see, e.g., WO’077 at ¶¶[00126], [0143]), and artisan would readily infer and at once envisage that routine lyophilization necessarily and inherently included the stage of primary drying (or sublimation) and the stage of secondary drying (or desorption). Regarding instant claim 6 and “wherein a freezing point of the mixed solvent containing water and the organic solvent is -60°C or more”, the freezing point of an 80% tert-butanol (“t-butanol/water 4:1”) (see, e.g., WO’077 at ¶[00143]) is understood to be -60°C or more as evidenced by Vessot (see, e.g., Vessot at 379 at col I at 1st partial ¶, Fig. 1, disclosing that 80% (w/w) TBA nucleated at -15 °C, and that 90% (w/w) TBA nucleated at -23°C, and therefore <80% (w/w) TBA would have a nucleation point higher than -15°C). Regarding instant claim 7 and t-butanol, the disclosed embodiment of WO’077 explicitly utilizes t-butanol (see, e.g., WO’077 at ¶¶[00114], [00122], [00126]). Regarding instant claims 8-9 and 11-13, WO’077 identifies that “HDP 30.1895” is a cyclic polypeptide with a Molecular weight of 1012.11, comprising 8 amino acids, comprising the non-natural amino acid residue of norvaline (see WO’077 at ¶[00122]), and wherein the cyclic peptide must necessarily and inherently exhibits some level of lipophilicity (see WO’077 at ¶[00122], reproduced in part below):
PNG
media_image1.png
264
283
media_image1.png
Greyscale
Regarding instant claim 10 and a “CLogP” of”25 or less”, “HDP 30.1895” as disclosed by WO’077 is understood to necessarily and inherently have a CLogP of 25 or less as evidenced by the CAS Registry number associated with the structure (see, e.g., CAS Registry Number 2130958-62-0 at page 4, showing a calculated LogP value of -3.046±0.00). Regarding instant claim 15, claim 15 has been rejected under 35 USC 112(b) and 112(d) above, and those discussions are incorporated into the instant rejection. Claim 15 is deemed anticipated for the reasons and facts applied to claim 1 above.
Accordingly, claims 1-2, 4-13, and 15 are anticipated by the prior art.
[Prior Art Rejection 02]
Claims 1-7 and 15-19 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being clearly anticipated by Kunz et al.6 (hereafter “Kunz2017”).
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
Kunz2017 discusses the art-recognized benefits of freeze-drying using organic solvents, including improving dissolution characteristics and drying rates (see, e.g., Kunz2017 at title, abs, 887 at col I-II at bridging ¶), and improving chemical stability of some active agents (see id. at 888 at col I at 1st ¶). Regarding instant claim 1, Kunz2017 discloses freeze-drying methods utilizing organic cosolvent systems (see, e.g., Kunz2017 at title, abs, Table 4 at 891). Specifically, Kunz2017 discloses at least two production methods comprising providing a mixed solution containing water, an organic solvent (i.e., either TBA or DMSO), and a substance to be freeze-dried (i.e., polyvinylpyrrolidone or “PVP”) as required by instant claim 1(1) (see, e.g., Kunz2017 at title, abs, Table 4 at 891), wherein the mixed solution is subjected to freeze-drying as required by instant claim 1(2) (see, e.g., Kunz2017 at title, abs), and wherein the organic solvent is present within the range of 68-99% by weight as required by claim 1 (see, e.g., Kunz2017 at title, abs, Table 4 at 891 noting that 70% TBA and 99% DMSO were utilized) in FDM, which is Freeze-Dry Microscopy, which necessarily, inherently, and implicitly involves freeze-drying (see, e.g., Kunz2017 at 889 at col II at § Freeze-Dry Microscopy, 890 at col II at § FDM Analysis to 891 at col II at 1st full ¶). Regarding instant claim 2, the combination of three components (see, e.g., Kunz2017 at Table 4 at 891), wherein PVP is subsequently combined with a previously tested solvent (see, e.g., Kunz2017 at Table 2 at 890), implies that PVP was mixed with the binary solvent, and one of ordinary skill in the art would at once envisage the step of adding PVP to either 70% TBA or 99% DMSO. Regarding claim 3, For the 70% TBA and PVP mixture, PVP is present at 50 mg/g (i.e., 0.05g/g), 70% TBA has a density of approximately 0.84 g/mL7, and therefore PVP is present at approximately ~4% w/v%8 (see, e.g., Kunz2017 at Table 2 at 890, Table 4 at 891). For the 99% DMSO mixture, PVP is present at 50 mg/g (i.e., 0.05g/g), 99% DMSO has a density of approximately ~1.1 g/mL9, and therefore PVP is present at approximately ~5 to ~5.5% w/v%10 (see, e.g., Kunz2017 at Table 2 at 890, Table 4 at 891). Accordingly, PVP is present within the range of 2 w/v% to 20 w/v% as required by instant claim 3. Regarding instant claim 4, critically “pre-freezing step” is not limited and is understood to include any step that occurs prior to the actual moment that the mixture is frozen (see, e.g., Specification filed 6/20/2023 at ¶¶[0059]-[0061]). Here, Kunz2017 discloses that the samples were cooled at a constant rate of 5°C/min, which occurred prior to freezing (see, e.g., Kunz2017 at 889 at col II at § Freeze-Dry Microscopy, 890 at col II at § FDM Analysis to 891 at col II at 1st full ¶; see esp. id. at 889 at 3rd full ¶). Regarding instant claim 5 and a drying step having a plurality of stages including a first and second stage, Kunz2017 discloses that the samples were cooled at a constant rate of 5°C/min, held for 10-minutes at isothermal equilibration at -55°C to ensure complete solidification, then placed under vacuum at 100 mTorr after 8 minutes of holding, and then the frozen solution was heated at 1°C/min (see, e.g., Kunz2017 at 889 at col II at § Freeze-Dry Microscopy, 890 at col II at § FDM Analysis to 891 at col II at 1st full ¶). Accordingly, the drying step included at least the vacuum at 100 mTorr after 8 minutes of holding at -55°C, and a second stage of drying wherein the frozen solution was heated at 1°C/min (see id). Regarding instant claim 6, the freezing point for all organic solvents tested is understood to be “-60°C or more” because all solutions were reported as frozen at least at -55°C (see, e.g., Kunz2017 at 889 at col II at § Freeze-Dry Microscopy, 890 at col II at § FDM Analysis to 891 at col II at 1st full ¶). Regarding instant claim 7, the sample of 70% TBA comprises t-butanol (see, e.g., Kunz2017 at title, abs, Table 4 at 891). Regarding instant claim 15, claim 15 has been rejected under 35 USC 112(b) and 112(d) above, and those discussions are incorporated into the instant rejection. Claim 15 is deemed anticipated for the reasons and facts applied to claim 1 above. Regarding instant claim 16, Kunz2017 discloses that the samples were cooled at a constant rate of 5°C/min, which occurred prior to freezing, down to -55°C, and that temperature was held for 10-minutes to ensure complete solidification (see, e.g., Kunz2017 at 889 at col II at § Freeze-Dry Microscopy, 890 at col II at § FDM Analysis to 891 at col II at 1st full ¶; see esp. id. at 889 at 3rd full ¶). Furthermore, the temperature for nucleation for 70% TBA is reported as between -16.2 and -22.3, and therefore the pre-freezing step is understood to satisfy the limitations of claim 16. Regarding instant claim 17, Kunz2017 discloses that the samples were cooled at 5°C/min, and held for 10-minutes at isothermal equilibration at -55°C to ensure complete solidification, then placed under vacuum at 100 mTorr after 8 minutes of holding, and then the frozen solution was heated at 1°C/min (see, e.g., Kunz2017 at 889 at col II at § Freeze-Dry Microscopy, 890 at col II at § FDM Analysis to 891 at col II at 1st full ¶). Critically, 100 mTorr is ~13.33 Pa (1 mTorr is ~0.1333 Pa). Regarding instant claims 18-19, Kunz2017 discloses that the samples were cooled at a constant rate of 5°C/min, held for 10-minutes at isothermal equilibration at -55°C to ensure complete solidification, then placed under vacuum at 100 mTorr after 8 minutes of holding, and then the frozen solution was heated at 1°C/min (see, e.g., Kunz2017 at 889 at col II at § Freeze-Dry Microscopy, 890 at col II at § FDM Analysis to 891 at col II at 1st full ¶). Accordingly, a first drying stage included at least the vacuum at 100 mTorr after 8 minutes of holding at -55°C, and a second stage of drying wherein the frozen solution was heated at 1°C/min (see id), wherein the sample would rise in temperature from -55°C to higher temperatures. Therefore, the drying temperatures were within the range of -60°C to 60°C; and the first stage occurred at -55°C which is within the range of -60°C to 0°C (see id).
Accordingly, claims 1-7 and 15-19 are anticipated by the prior art.
[Prior Art Rejection 03]
Claims 1-2, 4-11, and 13-15 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being clearly anticipated by US20140213781A1 as evidenced by CAS Reg. No. 1417629-02-7 (attached as 6 pages, June 3, 2026), and as further evidenced by Vessot et al.11,
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
US’781 pertains to cyclic tripeptide mimetics (see, e.g., US’781 at title, abs). Regarding instant claims 1-2 and 7, US’781 discloses that compound 312 was dissolved in 80% t-butanol/water and then lyophilized (see, e.g., US’781 at ¶[0109]) to yield a white solid (see, e.g., US’781 at ¶[0110]), wherein “80% t-butanol/water” would be readily understood (or otherwise at once envisaged) to refer to w/w %. Regarding instant claims 4-5, critically a “pre-freezing step” is not limited and is understood to include any step that occurs prior to the actual moment that the mixture is frozen (see, e.g., Specification filed 6/20/2023 at ¶¶[0059]-[0061]). US’781 discloses that the substance was lyophilized (see, e.g., US’781 at ¶¶[0109]-[0110]) and therefore an artisan would at once envisage routine and basic lyophilization steps. An artisan would readily appreciate that “lyophilization” necessarily and inherently involves a cooling step and at least two stages of drying as evidenced by Vessot (see, e.g., Vessot at 377 at col I-II at § Introduction, explaining that lyophilization “is the process by which the solvent is removed from a frozen solution by sublimation”, wherein “The freeze-drying process may be divided into three steps: Freezing, primary drying (or sublimation), and secondary drying (or desorption)”). Accordingly, in view of the primary reference disclosing that lyophilization was used (see, e.g., US’781 at ¶¶[0109]-[0110]), an artisan would readily infer and at once envisage that lyophilization necessarily included a cooling/freezing step, as well as primary drying (or sublimation), and secondary drying (or desorption) in view of the art-recognized definition and meaning of “lyophilization”. Regarding instant claim 6, the freezing point of an 80% tert-butanol is -60°C or more as evidenced by Vessot (see, e.g., Vessot at 379 at col I at 1st partial ¶, Fig. 1, disclosing that 80% (w/w) TBA nucleated at -15 °C, and that 90% (w/w) TBA nucleated at -23°C, and therefore <80% (w/w) TBA would have a nucleation point higher than -15°C). Regarding instant claims 8-11 and 13-14, US’781 discloses that compound 3 was dissolved in 80% t-butanol/water and then lyophilized (see, e.g., US’781 at ¶[0109]), wherein compound 313 is understood to be a peptide having some intrinsically extant level of liophilicity, which “has a cyclic structure”, non-natural amino acid residue(s), and an “N-substituted amino acid”14 (e.g., -NHR, wherein R represents an aryl, cycloalkyl having a substituent, etc.) as shown below:
PNG
media_image2.png
226
316
media_image2.png
Greyscale
15
Furthermore, Compound 3 is understood to have a molecular weight of approximately ~809 (see, e.g., US’781 at ¶¶[0108]-[0110]), and is understood to inherently possess a CLogP of approximately ~1.774, which is “25 or less” (compare instant claim 10 with Record for CAS Reg. No. 1417629-02-7 at page 4). Regarding instant claim 15, claim 15 has been rejected under 35 USC 112(b) and 112(d) above, and those discussions are incorporated into the instant rejection. Claim 15 is deemed anticipated for the reasons and facts applied to claim 1 above.
Accordingly, claims 1-2, 4-11, and 13-15 are anticipated by the prior art.
[Prior Art Rejection 04]
Claims 1-2, 4-7, and 15-20 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being clearly anticipated by Daoussi et al16 (hereafter “Daoussi”).
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
Daoussi pertains to freeze-drying methods utilizing 80% or 90% Tert-butanol (TBA) and an API17 (“Active Principle Ingredient”) (see, e.g., Daoussi at title, abs, 900 at § Introduction; see esp. id. at 900 at col II at 1st full ¶). Regarding instant claims 1-2 and 7, Daoussi discloses that they investigated two ternary mixtures comprising an API, water, and TBA, wherein the TBA utilized is understood to be 80% w/w and 90% w/w (see, e.g., Daoussi at 900 at col II at 1st full ¶, 901 at col I at 1st full ¶, Fig. 1 on 901, Figs. 2-5 on 902). Given the usage and disclosure of the TBA solvent separately from the API (see, e.g., Daoussi at 901 at Table 1), an artisan would readily envisage that the API was mixed with the 80% w/w and 90% w/w TBA solvents as required by instant claim 2. Daoussi identifies that the samples were subjected to freeze-drying, wherein the samples “were frozen under the same freezing protocol corresponding to a moderate freezing rate equal to 1 ◦C/min down to the final freezing temperature equal to −45 ◦C; then, the samples were maintained at this temperature during about 2h for a complete solidification of the product. Different sublimation protocols corresponding to three total gas pressures and four shelf temperatures were investigated” (see, e.g., Daoussi at 901 at col I at 1st full ¶). Regarding instant claims 4 and 16, critically a “pre-freezing step” is not limited and is understood to include any step that occurs prior to the actual moment that the mixture is frozen (see, e.g., Specification filed 6/20/2023 at ¶¶[0059]-[0061]). Here, Daoussi is understood to disclose a “pre-freezing” step, namely the step of lowing the temperature of the sample by “a moderate freezing rate equal to 1 ◦C/min down to the final freezing temperature equal to −45 ◦C” (see, e.g., Daoussi at 901 at col I at 1st full ¶). Regarding instant claim 5, Daoussi identifies that freeze-drying as disclosed comprises two drying stages, namely a “primary drying period” and a “secondary drying step” involving “increasing the shelf temperature” (see, e.g., Daoussi at 900 at col I at 1st ¶). Regarding claim 6, Daoussi identifies that both samples were frozen at least at a “final freezing temperature equal to −45 ◦C” (see, e.g., Daoussi at 901 at col I at 1st full ¶). Therefore, the freezing point of the mixed solvents must be -60°C or more. Regarding instant claim 15, claim 15 has been rejected under 35 USC 112(b) and 112(d) above, and those discussions are incorporated into the instant rejection. Claim 15 is deemed anticipated for the reasons and facts applied to claim 1 above. Regarding claim 17 and pressure ranges within 1 to 50 Pa, Daoussi discloses that three different pressures were tested for each sample, namely 6 Pa, 15 Pa, and 25 Pa (see, e.g., Daoussi at Fig. 4-5 on 902, 902 at col I-II at §§ 3.2). Regarding claim 18 and “drying temperature” within the range of -60°C to 60°C, Daoussi identifies that the samples were subjected to freeze-drying, wherein the initial temperature is −45 ◦C and four shelf temperatures were investigated (see, e.g., Daoussi at 901 at col I at 1st full ¶), including -10, -20, -30, and -40°C (see, e.g., Daoussi at fig. 1 on 901, Fig. 2-3 on 902, 901 at col I-II at § 3.1 to 902 at col I at 1st partial ¶). Regarding claim 19 and a drying temperature in the first stage of drying ranging from -60°C to 0°C, the first stage of drying is understood to be the “primary drying period” (see, e.g., Daoussi at 900 at col I at 1st ¶), which corresponds to the tested “shelf temperatures”; specifically, Daoussi identifies four shelf temperatures were investigated (see, e.g., Daoussi at 901 at col I at 1st full ¶), including -10, -20, -30, and -40°C (see, e.g., Daoussi at fig. 1 on 901, Fig. 2-3 on 902, 901 at col I-II at § 3.1 to 902 at col I at 1st partial ¶). Regarding claim 20 and a drying temperature in the second stage of the drying within a range of 0°C to 60°C, the second stage of drying is called the “desorption step”, and the start of the second stage begins after a critical moisture content occurs (see, e.g., Daoussi at 905 at col II at 1st partial ¶), and this is shown in the drying curves at Figure 11, which shows an inflection point and temperatures rising from sub -10° C up to just below 20°C (see, e.g., Daoussi at Fig. 11 on 904, 904 at col I at §§ 3.6.1 to §§ 3.6.2 “Determination from drying curves”). Therefore, a “drying temperature” in the second stage is understood to fall within the claimed range.
Accordingly, claims 1-2, 4-7, and 15-20 are anticipated.
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.
[Prior Art Rejection 05]
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Daoussi et al18 (hereafter “Daoussi”) as applied to claims 1-2, 4-7, and 15-20 above, and further in view of Drooge et al19 as evidenced by CAS Reg. No. 59865-13-3 (attached as 11 pages, June 3, 2026).
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
The teachings of Daoussi as applied to claims 1-2, 4-7, and 15-20, has been discussed above in a preceding rejection, and those teachings under 35 USC §102 are incorporated herein, and it is noted that anticipation is the epitome of obviousness. Benefits of Daoussi methodology: In addition to the teachings discussed above, Daoussi additionally teaches and directs artisans to utilize high amounts of TBA (e.g., 80% or 90% wt/wt) to desirably speed up drying rates during freeze-drying processes (see, e.g., Daoussi at 900 at col I at final ¶, 902 at col I at 1st partial ¶, 906 at col I-II at bridging ¶, 906 at col II at § 4, explaining that TBA/water+ solvent system led to shorter sublimation times - by a factor 10-11 - without affecting the most important end-used properties….” ). The reduction in time is understood to have economic benefits (see, e.g., Daoussi at 900 at col I at 1st ¶). In addition, the co-solvent system disclosed by Daoussi is understood to advantageously increase “API solubility in the liquid formulation” (see, e.g., Daoussi at 900 at col II at 1st full ¶). Accordingly, Daoussi reasonably informs artisans that the disclosed methodologies, including usage of 80% and 90% TBA, would desirably and advantageously increase API solubility and substantially reduce sublimation times by a factor of 10-11. Additional teachings are set forth below.
The disclosure of Daoussi differs from instant claims 3 and 8-14 as follows: Although Daoussi discloses methodologies presumably applicable to all APIs (Active Principle Agents) at various concentrations, Daoussi does not actually exemplify the freeze drying methods disclosed with cyclic peptides as required by instant claims 8-14 at a concentration as required by instant claim 3.
Drooge pertains to lyophilization methods and formulations applicable to cyclosporine A (CSA), which utilize TBA in water (see, e.g., Drooge at title, abs). Like the primary reference, Drooge also teaches that CSA had been previously combined with TBA/water formulations (see, e.g., Drooge at abs), but Drooge does not test nor disclose formulations utilizing more than about 40% v/v TBA in water (see, e.g., Drooge at 716 at col I at 1st ¶, Fig. 4 at 719). Regarding instant claim 3, Drooge directs artisans to make and use 10% w/w CSA formulations (see, e.g., Drooge at 716 at col I at 1st full ¶, Table 4 on 721). Regarding instant claims 8-14, Cyclosporine A20 is known in the art as a lipophilic, cyclic peptide having CLogP of approximately 3.00 (see, e.g., Drooge at Table 2 on 717), a molecular weight of approximately 1202.61, which comprises 11 amino acids, including an N-substituted21 “non-natural”22 amino acid of N(Me)Bmt(E), as evidenced by CAS Registry Number 59865-13-3:
PNG
media_image3.png
469
606
media_image3.png
Greyscale
Accordingly, claims 8-14 are satisfied by CSA. In sum, the pending claims are understood to be satisfied by the methodology of Daoussi wherein the API of Daoussi is simply substituted with the cyclosporine A as taught by Drooge.
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s):
First, the invention is the combination of known prior art elements (e.g., TBA, water, and the API of cyclosporine A) according to known methods (e.g., the freeze-drying method of Daoussi using either 80% or 90% TBA) to yield predictable results, namely a method of freeze-drying cyclosporine A having substantially reduced sublimation times as taught by Daoussi (see, e.g., MPEP 2143(I)(A), (G))23. Furthermore, each element would merely perform the same function as it does separately.
Second, or alternatively, the invention is the simple substitution of one known element (cyclosporine A) for another (i.e., the API or “Active Principle Ingredient”) in the known method of freeze-drying active principle ingredients disclosed by Daoussi, wherein such substitution would yield predictable results, namely a method of freeze-drying cyclosporine A having substantially reduced sublimation times as taught by Daoussi (see, e.g., MPEP 2143(I)(B), (G)).
Third, or alternatively, the invention is the use or application of the known technique of utilizing 80% or 90% TBA in water to facilitate freeze-drying of active principle ingredients by improving sublimation drying times and solubility as disclosed by Daoussi upon the known active principle ingredient of cyclosporine A (CSA), wherein the use of application of this technique upon CSA would be predicted and expected to desirably facilitate freeze-drying of CSA by improving sublimation drying times and solubility (see, e.g., MPEP 2143(I)(C), (D), (G))24.
Accordingly, for at least the rationales explained above, the instant claim scope is obvious.
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to utilize known methods with known reagents to obtain a known and predicted result with a reasonable expectation of success.
Accordingly, claims 1-20 are rejected as obvious in view of the prior art.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US2022/0411462 (Application 17/738,283) appears to disclose compounds related to the lipopeptide in the originally elected species (see, e.g., US’462 at title, abs, claims, passim).
US20230151060A1 (Application 17/773,733) appears to disclose compounds related to the lipopeptide in the originally elected species (see, e.g., US’060 at title, abs, claims, passim).
US4311712A teaches and discloses examples utilizing DPPC (Dipalmitoyl-phosphatidylcholine) and 3H-CP (3H-cortisol 21-palmitate) in t-butanol, then freezes the mixture, and removes t-butanol by freeze-drying (see, e.g., US’712 at Example 1 at col 4 at lines 30-60, Example 2 at col 4 at line 60 to col 5 at line 55). Although 100% t-butanol is utilized in the examples, US’712 identifies that water may optionally be added (see, e.g., US’712 at col. 3 at lines 47-60).
Teagarden et al.25 pertains to and discusses TBA + water mixtures for use in lyophilization, but primarily focuses on 20% or 40% w/w TBA (see, e.g., Teagarden at title, abs, 115 at § Introduction, Table 1 on 116, Fig. 3 on 121).
Kunz et al.26 (hereafter “Kunz2019”) pertains to freeze-drying methods utilizing organic co-solvents, including 70% tert-butanol (see, e.g., Kunz2019 at title, abs).
Kasper et al.27 (hereafter “Kasper”) pertains to methods of lyophilization, commonly optimized parameters, and the usage of non-aqueous cosolvents, such as TBA to advantageously increase drug solubility, accelerate sublimation rates, decrease reconstitution time, and improve product stability (see, e.g., Kasper at title, abs, passim; see esp. id. at 165 at col I at 3rd full ¶). Accordingly, the usage of TBA as a cosolvent was well-known and associated with numerous benefits circa 2013.
Yong Zhang et al.28 (hereafter “Zhang”) pertains to freeze-drying methods utilizing from 0% to 50% TBA with insulin (see, e.g., Zhang at title, abs, passim). Zhang identifies that insulin did not exhibit substantial rearrangement of secondary structure after rehydration using 50% TBA, suggesting that higher levels of TBA are stabilizing (see, e.g., Zhang at title, abs, passim).
Li et al.29 (hereafter “Li”) pertains to Tert-Butanol/water mixtures utilized with Soybean phosphatidylcholine (SPC), used in freeze-drying methods (see, e.g., Li at title, abs, 1404 at col I-II, passim; see esp. id. at Fig. 1 on 1406).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RANDALL L BEANE whose telephone number is (571)270-3457. The examiner can normally be reached Mon.-Fri., 7 AM to 2 PM ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G. Garyu can be reached at (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/RANDALL L BEANE/ Primary Examiner, Art Unit 1654
1 CAS Reg No. 2642640-82-0.
2 Cited in Requirement mailed 3/11/2026.
3 Vessot et al., A Review on Freeze Drying of Drugs with tert-Butanol (TBA) + Water Systems: Characteristics, Advantages, Drawbacks, Drying Technology, 30(4): 377–385, 2012; DOI:10.1080/07373937.2011.628133.
4 CAS Reg. No. 2130958-62-0, α-Amanitin, 1-L-aspartic acid-3-[(4R)-4,5-bis(acetyloxy)-L-isoleucine]-4-(2-mercapto-L-tryptophan)-, de-S-oxide (ACI).
5 Water is 1 mg/mL, T-butanol is ~0.78 mg/ml. Therefore, 80% t-butanol would be (0.78*.8)/(0.78*0.8 +1*0.2), or (0.624)/(0.824)*100, or ~75.7% wt/wt organic solvent.
6 Kunz et al. (2017), Freeze-Drying From Organic Cosolvent Systems, Part 1: Thermal Analysis of Cosolvent-Based Placebo Formulations in the Frozen State. J Pharm Sci. 2018 Mar;107(3):887-896. doi: 10.1016/j.xphs.2017.11.003. Epub 2017 Nov 10. PMID: 29133233.
7 TBA has a density of ~0.775 g/mL (pure TBA) and 1 g/mL (water), so 0.7(0.775) +0.3 is ~0.84 g/mL
8 w/v% = (C * density)*100 or (0.05*0.84)*100
9 DMSO has a density of ~1.1 g/mL (pure) and 1 g/mL for water, so 0.8(1.1) +0.3 is ~1.08 g/mL
10 w/v% = (C * density)*100 or (0.05*0.84)*100
11 Vessot et al., A Review on Freeze Drying of Drugs with tert-Butanol (TBA) + Water Systems: Characteristics, Advantages, Drawbacks, Drying Technology, 30(4): 377–385, 2012; DOI:10.1080/07373937.2011.628133.
12 Compound 3 is understood to be shown at US’781 at ¶[0108], wherein the protocol for making Compound 3 involves reacting Compound 3d as described (see ¶[0109]), which yields Compound 3, having a mass of ~808
13 Although ¶[0109] begins with Compound 3d, the reaction described yields Compound 3 (see ¶¶[0104]-[0110]).
14 Per Specification filed 6/20/2023 at ¶[0043], “unsubstituted (-NH2)” or “substituted (i.e., NHR…as in proline)”….such an amino acid having the substituted backbone amino group may be referred to as the “N-substituted amino acid”.
15 CAS Reg. No. 1417629-02-7; 2,6,9,13,20-Pentaazatetracyclo[22.2.2.26,9.214,17]dotriaconta-14,16,24,26,27,29-hexaene-19-carboxamide, N-[[4-(aminomethyl)phenyl]methyl]-3,12,21-trioxo-22-[[(phenylmethyl)sulfonyl]amino]-, (19S,22R)- (ACI).
16 Daoussi et al, Sublimation kinetics and sublimation end-point times during freeze-drying of pharmaceutical active principle with organic co-solvent formulations. Chemical Engineering Research and Design 2009, 87, 899–907.
17 The API utilized is not specifically disclosed, but is understood to be representative of pharmaceutical agents capable of acting as principle active agents.
18 Daoussi et al, Sublimation kinetics and sublimation end-point times during freeze-drying of pharmaceutical active principle with organic co-solvent formulations. Chemical Engineering Research and Design 2009, 87, 899–907.
19 Drooge et al, Incorporation of lipophilic drugs in sugar glasses by lyophilization using a mixture of water and tertiary butyl alcohol as solvent. J Pharm Sci. 2004 Mar;93(3):713-25. doi: 10.1002/jps.10590. PMID: 14762909.
20 CAS Reg. No. 59865-13-3; a.k.a., cyclo[Abu-Sar-N(Me)Leu-Val-N(Me)Leu-Ala-D-Ala-N(Me)Leu-N(Me)Leu-N(Me)Val-N(Me)Bmt(E)].
21 Per Specification filed 6/20/2023 at ¶[0043], “unsubstituted (-NH2)” or “substituted (i.e., NHR…as in proline)”….such an amino acid having the substituted backbone amino group may be referred to as the “N-substituted amino acid”.
22 “Non-natural amino acid” is understood to be any amino acid other than the “natural amino acids” enumerated at page 7 (see, e.g., Specification filed 6/20/2023 at ¶¶[0016]).
23 "[W]hen a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious."
KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 , 417 , 127 S. Ct. 1727 , 167 L. Ed. 2d 705 (2007) (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273 , 282 , 96 S. Ct. 1532 , 47 L. Ed. 2d 784 (1976)).
24 “If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.”
KSR Int'l v. Teleflex Inc., 550 U.S. 398, 415 (2007), at 417.
25 Teagarden et al., Practical aspects of lyophilization using non-aqueous co-solvent systems. Eur J Pharm Sci. 2002 Mar;15(2):115-33. doi: 10.1016/s0928-0987(01)00221-4. PMID: 11849908.
26 Kunz et al., Freeze-Drying From Organic Co-Solvent Systems, Part 2: Process Modifications to Reduce Residual Solvent Levels and Improve Product Quality Attributes. J Pharm Sci. 2019 Jan;108(1):399-415. doi: 10.1016/j.xphs.2018.07.002. Epub 2018 Jul 12. PMID: 30017885.
27 Kasper et al., Recent advances and further challenges in lyophilization. Eur J Pharm Biopharm. 2013 Oct;85(2):162-9. doi: 10.1016/j.ejpb.2013.05.019. Epub 2013 Jun 7. PMID: 23751601
28 Yong Zhang et al., Conformational and bioactivity analysis of insulin: freeze-drying TBA/water co-solvent system in the presence of surfactant and sugar. Int J Pharm. 2009 Apr 17;371(1-2):71-81. doi: 10.1016/j.ijpharm.2008.12.018. Epub 2008 Dec 24. PMID: 19136051.
29 Li et al., A novel method for the preparation of liposomes: freeze drying of monophase solutions. J Pharm Sci. 2004 Jun;93(6):1403-14. doi: 10.1002/jps.20055. PMID: 15124200.
Prosecution Insights