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
Acknowledgement is made that Instant Application 18/938,440, filed on 2024, Nov. 06 claims priority from Provisional Application 63/596,717, filed on 2023, Nov. 07. It is noted, however, that claim 5, claim 6, claim 9, and claim 10, are not supported by the Provisional Application and therefore do not receive the benefit of the earlier filing date.
Information Disclosure Statement
Applicant has elected not to submit a/an information disclosure statement(s) with the Instant Application.
Claim Objections
The following claims are objected to:
Claim 2 recites the formula of N-(2-acetoxtbenzoyl) ethyl guanidino acetate as “H2NC(=Ab)NHCH2COOC2H5.” The formula should be corrected to read “H2NC(=NAb)NHCH2COOC2H5”
Claim 5 recites the limitation “N-(2-acetoxtbenzoyl) ethyl guanidino acetate”, which should be correctly rewritten as “N-(2-acetoxybenzoyl) ethyl guanidino acetate.”
Appropriate action is required.
Claim Interpretation
Claim 18 recites the limitation, “which is for preventive measure before the sign of eczema shows up in a human subject in need thereof”. For the purposes of this examination, this limitation is interpreted to mean applying the medication prior to signs of itch or eczema e.g., prophylaxis.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 16 is 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 treating pain, itch, or eczema in a human subject by administering a composition comprising a guanidinoacetic acid derivative, does not reasonably provide enablement for a synergetic or synergistic effect when administering another pharmacological agent. 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/or use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
In this regard, the application disclosure and claims have been compared per the factors indicated in the decision In re Wands, 8 USPQ 2nd 1400 (Fed. Cir. 1988) as to undue experimentation. The factors include: (a) The nature of the invention; (b) The breadth of the claims; (c) The relative skill of those in the art; (d) Status of the prior art/predictability or unpredictability of the art (e) The amount of direction or guidance presented; (f) The presence or absence of working examples and (g) The quantity of experimentation necessary. Each factor is addressed below on the basis of comparison of the disclosure, the claims and the state of the art in the assessment of undue experimentation.
The nature of the invention: The invention is directed to a method of treating paint, itch, or eczema in a human subject in need thereof, comprising administering to the subject a composition comprising a guanidinoacetic acid derivative.
The breadth of the claim: The scope of the claim includes providing a synergetic or synergistic effect when administering another pharmacological agent with the guanidinoacetic acid derivative.
The relative skill of those in the art: The level of skill is high comparable to that of an M.D. or Ph.D.
Status of the prior art/predictability or unpredictability of the art: It is known in the art that a synergetic effect between drug combinations is hard to acquire and quantify (see Meyer. Charting the Fragmented Landscape of Drug Synergy. Trends in Pharmacological Sciences. 2020, 41(4), 266-280. doi.org/10.1016/j.tips.2020.01.011). Meyer teaches the three foundational principles of synergy, as it relates to medicinal combinations: 1. Dose Equivalence principle (DEP), which asserts if the effect of reducing one drug’s concentration can be compensated for by adding a second drug at a constant ratio; there is no synergy (also called additivity); 2. Multiplicative Survival Principle (MSP), which takes a probabilistic approach to synergy asserting the probability of being unaffected by each drug individually (U1,U2) is independent. Therefore, the probability of being unaffected by the combination (U1,2) is equal to the product of the single drug probabilities (U1,2=U1*U2). If the percent of the population unaffected by the combination is less or more than this product, the combination is synergistic or antagonistic, respectively; and 3. Highest Single Agent (HAS), which defined synergy as the difference between a combination’s effect and the most efficacious single agent (page 266, paragraph 1). Meyer further teaches modern expansion of the classical synergy frameworks, comprising implicit assumptions and limitations due to no existing standardized criteria for comparison (page 268, Table ). There are some drug combinations that meet the criteria of some principals but fail others. For example, Meyer teaches an antimalarial combination in which three samples at different doses are all antagonistic by MSP and DEP, while the combination is synergistic by the mean over the whole dose-response surface (HAS) (page 271, paragraph 2). Meyer suggests that if synergy is a property of drug pairs, then the optimal drug concentrations should be determined based solely on maximizing efficacy with therapeutically tolerable doses. However, if synergy is a property of particular drug concentrations, then optimal doses should be selected based on both synergy and efficacy of a particular dose pair. The implications of these divergent worldviews have not been previously discussed, yet they represent a critical fault-line in the field with far-reaching ramifications for the discovery and deployment of combination therapy (page 271, paragraph 2). Accordingly, the unpredictability and burden of formulating a synergetic drug composition is high. One of ordinary skill in the art could not accurately predict the correct concentration of two drugs necessary to form a synergetic effect.
The amount of direction or guidance presented: The specification does not provide any guidance in terms of providing a synergetic effect with the claimed guanidinoacetetic acid derivatives and the additional pharmacological agents for treating pain, itch, or eczema. The specification further does not provide any references to indicate such an effect is possible. It is known in the art that many of the disclosed synergetic pharmacological agents undergo different modes of action. For instance, hydrocortisone is an anti-inflammatory agent and hydrogen peroxide is an oxidizing agent. As such, one of ordinary skill wouldn’t anticipate hydrocortisone to have similar synergetic properties as hydrogen peroxide.
The present or absence of working examples: No working examples are provided for synergetic effects of the claimed guanidinoacetic acid derivatives for treating pain, itch, or eczema with any of the synergetic pharmacological agents, for example, in a patient in the specification. The applicant has not provided any competent evidence or disclosed any tests that are highly predictive for the synergetic effects of the instant composition. Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved." See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The quantity of experimentation necessary: The quantity of experimentation would be an undue burden to one of ordinary skill in the art. Thus, factors such as “sufficient working examples,” “the level of skill in the art" and "predictability," etc. have been demonstrated to be sufficiently lacking in the instant case for the instant method claim”. In view of the breadth of the claims, the chemical nature for the instant claims and unpredictability of providing a synergetic effect, and the lack of working examples regarding the activity as claimed, one skilled in the art would have to undergo an undue amount of experimentation to use the instantly claimed invention commensurate in scope with the claims.
In consideration of the Wands factors, it is apparent that there is undue experimentation because of variability in prediction of outcome that is not addressed by the present application disclosure, examples, teaching and guidance presented. Absent factual data to the contrary, the amount and level of experimentation needed is undue.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claim(s) 1-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yu (US 2022/0323388 A1, published 2022, Oct. 13) in view of Wyss (Creatine and Creatine Metabolism. Physiological Reviews, 2000, 80(3), 1107-1213), as motivated by Jäger (Analysis of the Efficacy, Safety, and Regulatory Status of Novel Forms of Creatine. Amino Acids, 2011, 40, 1369-1383. DOI 10.1007/s00726-011-0874-6), and in view of Semeredi (Guanidinoacetic Acid with Creatine Compared with Creatine Alone for Tissue Creatine Content, Hyperhomocysteinemia, and Exercise Performance: A Randomized, Double-Blind Superiority Trial. Nutrition, 2019, 57, 162-166).
Claim 1 is directed to a method for treating pain, itch, or eczema in a human subject in need thereof, the method comprising administering to the human subject a composition comprising a guanidinoacetic acid derivative of Formula I
H2NC(=NR1)NHCH2COR2 (Formula I)
wherein,
R1 is an acyl radical selected from the group consisting of acetyl, propanoyl, isobutanoyl, benzoyl, phenylacetyl, 2-acetoxybenzoyl, and pyroglutamyl;
R2 is OR3; and
R3 is methyl or ethyl.
Yu teaches creatine, its derivatives, compositions, and methods of use thereof, including topical or system administration to treat pain, itch, or eczema, or inflammation associated with a cosmetic or medical condition, disorder, or disease in a human subject (title, abstract). The creatine derivatives are compounds of Formula II (page 1, paragraph 0009)
H2NC(=NR1)N(CH3)CH2COR2 (Formula II)
wherein
R1 is H, or an acyl radical having up to 29 carbon atoms;
R2 is H, OR3, NHR4, or any other amino group containing radical having up to 10 carbon atoms;
R3 is H, an alkyl aralkyl, or aryl radical, wherein the alkyl aralkyl or aryl radical has up to 19 carbon atoms; and
R4 is H, OH, an alkyl, aralkyl, aryl, or acyl radical, wherein the alkyl, aralkyl, aryl or acyl radical has up to 19 carbon atoms, with a proviso that R2 is not OH when R1 is H.
The difference between Yu and the Instant Application is that Yu fails to teach derivatives of guanidinoacetic acid to treat pain, itch, or eczema. For example, Yu fails to teach any embodiment wherein the “N(CH3)” of Formula II is “NH.”
However, Wyss teaches creatine metabolism and biosynthesis, whereby guanidinoacetic acid is a direct metabolic precursor to creatine (page 1112, Figure 4). Systemic guanidinoacetic acid is taken up by multiple organs, including the liver, pancreas, testis, and kidneys, wherein it is converted to creatine through enzymatic methylation by guanidinoacetate N-methyltransferase (GAMT) (page 1112, Figure 4).
One of ordinary skill in the art would have been motivated to combine the above teachings because creatine is known to have low aqueous solubility, leading to early efforts to identify new forms of creatine with improved water solubility and bioavailability (see Jäger). Additionally, Semeredi teaches oral administration of a 3:1 mixture of creatine-guanidinoacetic acid has elevated creatine concentration in tissue compared to equimolar creatine alone (abstract). Therefore, said skilled artisan would have had a reasonable expectation of success in administering guanidinoacetic acid to enhance systemic levels of creatine, thereby effectively treating pain, itch, or eczema.
Claims 2-3 are directed to the method of claim 1, wherein the guanidinoacetic acid derivative is selected from the group consisting of e.g., N-acetyl ethyl guanidino acetate (H2NC(=NAc)NHCH2COOC2H5).
Yu teaches compound C15 as N-acetyl ethyl creatinate (H2NC(=NAc)N(CH3)CH2COOC2H5) (page 3, Table 1, entry 6).
Claim 4 is directed to the method of claim 1, wherein the composition comprises N-acetyl methyl guanidino acetate (H2NC(=NAc)NHCH2COOCH3).
Yu teaches N-acetyl methyl creatinate (H2NC(=NAc)N(CH3)CH2COOCH3) (page 15, claim 32, entry 2).
Claim 5 is directed to the method of claim 1, wherein the composition comprises N-(2-acetoxybenzoyl) ethyl guanidino acetate (H2NC(=NAb)NHCH2COOC2H5).
Yu teaches compound C26 as N-2-acetoxybenzoyl ethyl creatinate (H2NC(=NAb)N(CH3)CH2COOC2H5) (page 3, Table 1, entry 17).
Claim 6 is directed to the method of claim 1, wherein the composition comprises N-phenylacetyl ethyl guanidino acetate (H2NC(=NPc)NHCH2COOC2H5).
Yu teaches N-phenylacetyl ethyl creatinate (H2NC(=NPc)N(CH3)CH2COC2H5) (page 15, claim 32, entry 1).
Claims 7-10 are directed to the method of claim 1, wherein the composition comprises at least 1%, about 1%-10%, about 3%, or about 5% by weight or volume, based on a total weight or volume of the composition, of the guanidinoacetic acid derivative of Formula (2).
Yu teaches a topical composition of the invention comprises about 1% to about 10% by weight or volume, based on a total weight or volume of the composition, of creatine or a derivative thereof for Formula I or a pharmaceutically acceptable salt thereof or a solvate thereof, e.g., about 1%, about 3%, about 5%, or about 10%, or any number in between (page 4, paragraph 0063).
Claim 11 is directed to the method of claim 1, wherein the composition is topically administered.
Yu teaches compositions comprising creatine derivatives of Formula II can be formulated for topical administration (abstract).
Claim 12 is directed to the method of claim 1, wherein the composition is systemically administered.
Yu teaches compositions comprising creatine derivatives of Formula II can be formulated for system administration, including oral and parenteral injections (page 4, paragraph 0064).
Claim 13 is directed to the method of claim 12, wherein the composition is administered by subcutaneous injection.
Yu teaches the parenteral injections comprising creatine derivatives of Formula II can be administered by subcutaneous injection (page 4, paragraph 0064).
Claims 14-15 are directed to the method of claim 1, wherein the method provides anti-pain effect or treats itch or eczema.
Yu teaches the compositions comprising creatine derivatives of Formula II are used to treat pain, itch, or eczema (abstract).
Claim 16 is directed to the method of claim 1, wherein the method further comprises administering another pharmacological agent to provide synergetic or synergistic effect, and the pharmacological agent is selected from the group consisting of acetaminophen, 2-acetoxybenzoic acid; benzophenone; betamethasone dipropionate; butoconazole; caffeic acid; caffeine; clobetasol propionate; clotrimazole; dapsone; erythromycin; gluconic acid; gluconolactone; glucuronic acid; glucuronolactone; glycolic acid; hydrocortisone; hydrocortisone 21-acetate; hydrocortisone 17-butyrate; hydrocortisone 17-valerate; hydrogen peroxide; hydroquinone; kojic acid; lactic acid; mandelic acid; minoxidil; retinal; 13-cis-retinoic acid; retinoic acid; retinol; retinyl acetate; retinyl palmitate; and triamcinolone acetonide.
Yu teaches compositions comprising creatine derivatives of Formula II can be used in combination with another pharmacological agent that can be administered simultaneously or sequentially, to provide synergetic, synergistic, or enhanced effects (page 6, paragraph 0089). Examples of pharmacological agents suitable for use include, but are not limited to acetaminophen, 2-acetoxybenzoic acid; benzophenone; betamethasone dipropionate; bupivacaine; butoconazole; caffeic acid; caffeine; clobetasol propionate; clotrimazole; dapsone; erythromycin; gluconic acid, gluconolactone, glucuronic acid, glucuronolactone, glycolic acid; hydrocortisone; hydrocortisone 21-acetate, hydrocortisone 17-butyrate, hydrocortisone 17-valerate, hydrogen peroxide; hydroquinone; kojic acid; lactic acid; mandelic acid; minoxidil; retinal; 13-cis-retinoic acid; retinoic acid; retinol; retinyl acetate; retinyl palmitate; and triamcinolone acetonide (page 6, paragraph 0089).
Claim 17 is directed to the method of claim 1, wherein the eczema is selected from the group consisting of atopic eczema and inflammatory eczema.
Yu teaches the compositions comprising creating derivatives of Formula II are therapeutically effective for treating inflammatory disorders of the immune system, inter alia, which includes inflammatory eczema (page 6, paragraph 0100).
Claim 18 is directed to the method of claim 15, which is for preventive measure before the sign of eczema shows up in a human subject in need thereof, wherein the method comprises administering to the human subject a composition comprising a guanidinoacetic acid derivative selected from the group consisting of N-acetyl ethyl guanidinoacetate and N-acetyl methyl guanidinoacetate, and without being combined with an anesthetic.
Yu teaches N-acetyl ethyl creatinate (H2NC(=NAc)N(CH3)CH2COOC2H5) (page 15, claim 32, entry 1) and N-acetyl methyl creatinate (H2NC(=NAc)N(CH3)CH2COOCH3) (page 15, claim 32, entry 2) in pharmaceutical compositions for cutaneous injection for the treatment of pain or itch or eczema in a human subject in need thereof, whereby the term “treatment” includes prophylaxis (page 2 paragraph 0033). The compounds are taught to work with or without other pharmacological agents (page 1, paragraph 0008).
Conclusions
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/P.A./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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