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 .
Election/Restrictions
Applicant’s election of Group I in the reply filed on July 6, 2026, is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 25-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim Objections
Claim 1 is objected to because of the following informalities: the word “of” is missing in line 1, which should read “purification of a tripeptide”. Appropriate correction is required.
Claim 3 is objected to because of the following informalities: the -OH at the carboxy terminus of the tripeptide is cutoff. Appropriate correction is required. The structure is interpreted according to the formula on page 6 of the specification.
Claims 9 and 21 are objected to because of the following informalities: in claim 9, line 1 “step b)” appears to be a typographical error and should be “step c)”. Appropriate correction is required. Dependent claim 21 is objected to for the same reason.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-9, 15-22, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over IDKOWIAK-BALDYS et al. (US 2021/0338557 A1; hereafter “IDKOWIAK-BALDYS”) in view of the laboratory protocols, review guides and textbook excerpts cited as NPL references U-X on page 1 and U-V on page 2 of the attached PTO-892.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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.
Determining the scope and contents of the prior art.
IDKOWIAK-BALDYS teaches peptides derived from human growth factor GDF-11 wherein one or more amino acid residues have been oxidized that are useful for improving one or more signs of dermatological aging when topically applied to human skin, for treating a variety of dermatological disorders, and for improving the overall health of skin. The peptides are capable of increasing collagen and/or hyaluronic acid (HA) production of skin cells and therefore will have a beneficial effect on reducing the appearance of aging on skin (e.g., diminishing the appearance of wrinkles and/or fine lines, tightening sagging skin, thickening thinning skin, evening skin tone, treating hyperpigmentation and unwanted pigmentation, etc.) ([0009]). The peptides include tripeptides of instant formula (I) including formula (I-A) ([0012]):
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Ascertaining the differences between the prior art and the claims at issue.
IDKOWIAK-BALDYS does not teach a method of purifying the tripeptides using acidification and precipitation.
Resolving the level of ordinary skill in the pertinent art.
The prior art teaches a routine, well-established purification technique called recrystallization that is described in numerous guides and even taught in undergraduate organic chemistry teaching laboratories (see laboratory protocols and review guides in NPL references U-X page 1 and U page 2 on PTO-892). Recrystallization is a purification technique, comprising dissolving a solid, and then changing solution conditions to allow a solid to re-form. In this technique, an impure compound is dissolved to yield a solution containing both the desired compound and impurities. The solution conditions are changed, the desired compound crystallizes or precipitates and the impurities remain in solution. A filtration process is used to separate the desired pure solid form from the liquid impurities. Solubility curves can be used to predict the outcome of a recrystallization procedure. The protocol comprises parameters that can be optimized through routine experimentation, including solvent selection, crystallization method (solvents and temperature) and filtration.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to subject the tripeptide Ac-Met(O2)-Val-Val-OH taught by IDKOWIAK-BALDYS to the general method of recrystallization for purification taught and well-established in the prior art (see laboratory protocols in NPL references U-X page 1 and UV page 2 on PTO-892). Routine optimization of the recrystallization according to the prior art would yield a method comprising dissolving the tripeptide in aqueous solution, acidification to promote precipitation, and separation of the solid tripeptide from the liquid. The rationale for obviousness is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention (MPEP § 2143.01(G)). The relevant findings for this rationale are as follows.
(1) There was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference or to combine reference teachings. In the instant case, IDKOWIAK-BALDYS teaches that the Ac-M(O)2VV tripeptide increases pro-collagen I acid production in human dermal fibroblast (Example 1, Table 14, [0113]) and increases hyaluronic acid production in full thickness skin model assays (Example 2, Table 15). IDKOWIAK-BALDYS teaches topical compositions for cosmetic and dermatological use comprising the Ac-M(O)2VV tripeptide as an active ingredient ([0053]-[0072]). The tripeptide may be used for (a) treatment, reduction, and/or prevention of fine lines or wrinkles; (b) reduction of skin pore size; (c) improvement in skin thickness, plumpness, and/or tautness; (d) improvement in skin smoothness, suppleness and/or softness; (e) improvement in skin tone, radiance, and/or clarity; [0083] (f) improvement in procollagen, and/or collagen production; (g) improvement in maintenance and remodeling of elastin; (h) improvement in skin texture and/or promotion of retexturization; (i) improvement in skin barrier repair and/or function; (j) improvement in appearance of skin contours; (k) restoration of skin luster and/or brightness; (l) replenishment of essential nutrients and/or constituents in the skin; (m) improvement of skin appearance decreased by aging and/or menopause; (n) improvement in skin moisturization; (o) increase in skin elasticity and/or resiliency; (p) treatment, reduction, and/or prevention of skin sagging; (q) improvement in skin firmness; and (r) reduction of pigment spots and/or mottled skin; and (s) improvement of optical properties of skin by light diffraction or reflection ([0077]-[0096]). Given that IDKOWIAK-BALDYS teaches that the Ac-M(O)2VV tripeptide possesses many properties that are advantageous for cosmetic and dermatological use, one of ordinary skill in the art would have been motivated to develop a purification protocol to yield a pure tripeptide that can be formulated in a cosmetic or dermatological composition. Therefore, there was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference or to combine reference teachings.
(2) There was reasonable expectation of success. One of ordinary skill in the art would predict that a recrystallization method in which an impure Ac-M(O)2VV tripeptide is dissolved to yield a solution containing both the Ac-M(O)2VV tripeptide and impurities, the solvent and temperature conditions are adjusted to precipitate the Ac-M(O)2VV tripeptide, and a filtration process is used to separate the pure Ac-M(O)2VV tripeptide solid form from the liquid impurities would be successful and obtainable by routine experimentation in view of the laboratory protocols and review guides in NPL references U-X page 1 and U page 2 on PTO-892. See for example the following flow chart in the guide titled A4 Recrystallization (NPL V page 1, PTO-892)
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Therefore, there was a reasonable expectation of success.
(3) Whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness. The specification presents evidence that tripeptide Ac-Met(O2)-Val-Val-OH can be isolated by dissolving in aqueous LiOH at pH 9, lowering the pH to 2 by the addition of HCl, and cooling to 4° C to yield a precipitant (Example 1), and by dissolving in aqueous LiOH at pH 9, heating to reflux, lowering the pH to 2 by the addition of HCl, and cooling to room temperature to yield a precipitant (Example 2). The same conditions do not yield precipitants for comparison tripeptides that fall outside of the claimed formula (I). These results are consistent with the teaching in the prior art that solvent conditions and temperature can be optimized for the desired compound and that conditions for one compound are not necessarily the same as for other compounds with different solubility profiles. As a result, these results are expected, not unexpected in view of the prior art. Furthermore, there is no evidence that the precipitant formed is purified to an extent that is of statistical or practical significance. As a result, the data in the specification is not evidence of unexpected beneficial results. Finally, the examples in the specifications are not commensurate in scope with the claims, which include the broad Formula (I) and a broad range of temperatures and solvent conditions. For all of these reasons, the data in the specification does not constitute an unexpected result sufficient to overcome a prima facie case of rejection.
The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
Regarding claim 1, the method would be a purification method of the Ac-Met(O2)-Val-Val-OH tripeptide taught by IDKOWIAK-BALDYS, which is a tripeptide of formula (I) where R1 is CH3, and R2 and R3 are C3 alkyl groups. Step a) of claim 1 would be satisfied by preparing the Ac-Met(O2)-Val-Val-OH tripeptide as taught by IDKOWIAK-BALDYS.
Regarding step b), the guide titled A4 Recrystallization (NPL V page 1, PTO-892) states that the solvent should be chosen through a recommendation in the literature (A4.1, page 156). Water is listed as an option in the table of possible suitable solvents (A4.10, page 163). The guide also states that the solvent can be selected through routine experimentation (A4.10, pages 163-4, bridging paragraph). This is corroborated by guide published by Mettler Toledo (NPL U page 1, PTO-892) in the section entitled Step 1 on page 3. The examples in IDKOWIAK-BALDYS indicate that Ac-Met(O2)-Val-Val-OH tripeptide is soluble in aqueous media. As a result, POSITA would select water as the starting solvent for the recrystallization method.
Regarding steps c and d), the guide published by Mettler Toledo (NPL U page 1, PTO-892) states that the next step is crystallization and that one method for inducing crystallization is through an acid/base neutralization (section entitled D. Reaction (Precipitation) Recrystallization on page 5). In this method, the progressing acid/base neutralization increases supersaturation of the solute, which eventually recrystallizes. Lowering pH of an aqueous solution to 2 by the addition of HCl to induce precipitation is illustrated by the laboratory protocols for other compounds published by Robertson (NPL U page 2, PTO-892) on page 8, para. 5 and University of Illinois (NPL X page 1, PTO-892) on page 1, para. 7. POSITA would recognize that lowering the pH of a Ac-Met(O2)-Val-Val-OH tripeptide solution would result in protonation of the carboxy group, which would reduce solubility of the tripeptide and lead to precipitation. See the textbook section Amino Acids and Peptides (NPL V page 2, PTO-891) which states that “if an amino acid is dissolved in water which is held at pH = 2, the solution is a stronger acid than the carboxylic acid which would be formed by transferring a proton to the carboxylate ion” (pages 1-2, bridging paragraph). As a result, the step of lowering the pH to 2 and forming a precipitant is obvious.
Regarding step e, Mettler Toledo teach that the final step is filtration to separate the pure solid from the impurities in the liquid phase (section titled Step 6: Solid/Liquid Separation, page 7):
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For these reasons, claim 1 is prima facie obvious over the prior art.
Regarding claims 2-3, Ac-Met(O2)-Val-Val-OH tripeptide taught by IDKOWIAK-BALDYS, which is a tripeptide of formula (I) wherein R1 is CH3, and R2 and R3 are C3 alkyl groups isopropyl.
Regarding claims 4 and 15, POSITA would recognize that lowering the pH of a Ac-Met(O2)-Val-Val-OH tripeptide solution would result in protonation of the carboxy group, which would reduce solubility of the tripeptide and lead to precipitation. See the textbook section Amino Acids and Peptides (NPL V page 2, PTO-891) which states that “if an amino acid is dissolved in water which is held at pH = 2, the solution is a stronger acid than the carboxylic acid which would be formed by transferring a proton to the carboxylate ion” (pages 1-2, bridging paragraph). POSITA would predict based on this general understanding of acid-base chemistry of peptides and amino acids that a pH above 2 would be required to solubilize the tripeptide at the beginning of the procedure. Above pH 2 overlaps with the claimed range of about pH 3. The optimal pH would be determined by routine experimentation. Regarding claim 4, POSITA would understand that it is routine to adjust the amount of water in an aqueous solution. Regarding claim 15, POSITA would understand that it is routine to use bases to increase pH of an aqueous solution.
Regarding claims 5-8 and 16-20, the prior art guides and laboratory protocols on recrystallization all teach the use of temperature in the solubilizing and precipitation steps of the method. Sandtorv (NPL W page 1, PTO-892) teaches that because most solids have a better solubility at higher temperatures, saturation or almost saturation can be achieved at high temperature (usually the boiling temperature of the solvent), and that supersaturation and crystallization can be achieved by slowly cooling to room temperature (page 1, para. 2). Mettler Toledo (NPL U page 1, PTO-892) teaches that a large amount of solute can be dissolved at high temperature and due to lower solubility at low temperature, controlled cooling can initiate recrystallization (section titled Step 2A: Cooling Recrystallization, page 4). The guide titled A4 Recrystallization (NPL V page 1, PTO-892) teaches that the desired compound should be dissolved at high temperature and then cooled to promote crystallization (Figure A4.1 flow chart). The guide states that heating and solubilizing can be performed with close to boiling solvent (Section A4.1, page 2). The guide states that cooling can be performed at room temperature on a non-heat-conducting surface to permit a slow rate of cooling or by swirling the flask in a beaker of water at room temperature or in an ice bath (Section A4.4, page 4).
MPEP § 2144.05(II)(A) states: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)
In the instant case, it would have been routine optimization to arrive at the claimed invention of temperature for claimed steps b) and d) because the claimed parameters of temperature are recognized as a result-effective variable, i.e., a variable which achieves a recognized result. There would have been a reasonable expectation of success to arrive at the claimed temperature for step b) of between 10 and 30°C recited in claim 5, more than 80° C recited in step 7, ambient recited in claim 16, between 80 and 100°C recited in claim 18, and reflux recited in claim 19 because the prior art range of heated to boiling taught by Sandtorv, Mettler Toledo and A4 Recrystallization overlaps with the claimed ranges. Likewise, there would have been a reasonable expectation of success to arrive at the claimed temperature for step d) of below 30°C recited in claim 6, between 30 and 0° C recited in step 8, between 30 and 1°C recited in claim 17, and between 25 and 0°C recited in claim 20 because the prior art range of room temperature to ice bath taught by Sandtorv, Mettler Toledo and A4 Recrystallization, overlaps with the claimed ranges.
Regarding claims 6, 7, 9 and 21, lowering pH of an aqueous solution to 2 by the addition of HCl to induce precipitation is illustrated by the laboratory protocols published by Robertson (NPL U page 2, PTO-892) on page 8, para. 5 and University of Illinois (NPL X page 1, PTO-892) on page 1, para. 7. As a result, POSITA would select HCl, a readily available strong acid that is commonly used in peptide laboratories to lower the pH of the aqueous tripeptide solution. Regarding claim 7, the presence of acid would render the composition of step a) to an acidified form.
Regarding claim 22, IDKOWIAK-BALDYS teaches that the Ac-M(O)2VV tripeptide is an oxidized derivative of Ac-MVV, wherein the methionine side chain is oxidized to M(O)2 ([0009]). Ac-MVV is a species of formula (I0) wherein R1 is CH3, and R2 and R3 are C3 alkyl groups isopropyl.
Regarding claim 24, it would have been obvious to formulate the resulting tripeptide with a cosmetically acceptable carrier to yield a cosmetic composition containing the Ac-M(O)2VV tripeptide as an active agent. POSITA would have been motivated to do so given that IDKOWIAK-BALDYS teaches topical compositions for cosmetic and dermatological use comprising the Ac-M(O)2VV tripeptide as an active ingredient ([0053]-[0072]).
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over IDKOWIAK-BALDYS et al. (US 2021/0338557 A1; hereafter “IDKOWIAK-BALDYS”) in view of the laboratory protocols, review guides and textbook excerpts cited as NPL references U-X on page 1 and U-V on page 2 of the attached PTO-892 as applied to claims 1-9, 15-22, and 24 above, and further in view of Sjöberg et al. (Methionine oxidation by hydrogen peroxide in peptides and proteins: A theoretical and Raman spectroscopy study. Journal of Photochemistry and Photobiology B: Biology, Volume 188, November 2018, Pages 95-99; hereafter SJÖBERG).
Regarding claim 23, IDKOWIAK-BALDYS teaches that the Ac-M(O)2VV tripeptide is an oxidized derivative of Ac-MVV, wherein the methionine side chain is oxidized to M(O)2 ([0009]). Ac-MVV is a species of formula (I0) wherein R1 is CH3, and R2 and R3 are C3 alkyl groups isopropyl. IDKOWIAK-BALDYS does not teach a method for oxidizing the methionine in Ac-MVV to yield the Ac-M(O)2VV tripeptide. SJÖBERG teaches that hydrogen peroxide can be used to oxidize methionine in peptides (abstract). Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to make the Ac-M(O)2VV tripeptide from Ac-MVV by oxidizing with hydrogen peroxide.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA M MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 8:30 am - 5 pm.
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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.
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CHRISTINA M MARCHETTI BRADLEY
Primary Examiner
Art Unit 1654
/CHRISTINA M MARCHETTI BRADLEY/Primary Examiner, Art Unit 1654
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