DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AlA first to invent provisions.
Status of Application, Amendments and/or Claims
The amendment and Applicant’s arguments, filed 13 June 2025, have been entered in full. Claims 1-6, 10-12, 16 and 17 are withdrawn from consideration as being drawn to a non-elected invention. Claims 7-9, 13-15, 18-21 are canceled. Claims 23, 24 and 27 are amended. Claims 22-27 are under examination.
Withdrawn Objections And/Or Rejections
The rejection to claims 23, 24 and 27 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre- AIA ), First paragraph, Written description, New Matter, as set forth at pages 4-6 of the previous Office Action (13 December 2024), is withdrawn in view of the amendment (13 June 2025).
The rejection to claims 23, 24 and 27 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as set forth at pages 6-7 of the previous Office Action (13 December 2024), is withdrawn in view of the amendment (13 June 2025).
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 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.
Claims 22, 23, 25 and 26 remain rejected under pre-AlA 35 U.S.C. 103 as being unpatentable over Ranby (US 2005/0187158, published 25 August 2005) in view of Powell (US 4,929,442, published 29 May 1990). The basis for this rejection is set forth in the prior Office Action (13 December 2024, pages 7-11).
APPLICANT’S ARGUMENTS:
Applicant discusses claim 22 and the pending rejection. Applicant argues that
no single reference is asserted in the Action to teach topical application of both erythropoietin (EPO) and fibronectin (FN) in a gel.
Applicant argues that the Inventor has found, unexpectedly, that applying both EPO and FN provide synergistic benefits, which has not been seen, performed, or expected by others. Applicant argues that the Examples demonstrate that the combination of EPO and FN provide more than additive effects that are synergistic for increasing the rate of wound healing, increasing hydroxyproline (indicating collagen presence), increasing microvascular density, and increasing VEGF.
Applicant argues that it was asserted in Office Actions in some of the parent cases that the results were merely additive. Applicant submits that the Office did not properly take into account the baseline established by the control samples so that the additive effect can be properly calculated and not artificially inflated. Applicant maintains that the Office artificially inflated the calculation for what an additive effect would be. Applicant argues that to properly determine the additive effect, the improvements over the baseline induced by erythropoietin and fibronectin individually should be compared to the improvement over the baseline for the combination of erythropoietin and fibronectin. Applicant argues that the assertion by the Office Action that there was no synergy is technically incorrect as the “additive effect” numbers asserted in the Office Action were incorrectly too high.
Applicant discusses Example 2 (Wound Healing). Applicant argues that significant statistical difference in the percentage of wound healing was recorded from day 6 to day 12 of the experiment between mice treated with EPO or FN to those treated by vehicle. Applicant argues that the combination treatment with EPO and FN resulted in significant statistical differences in wound healing as early as 4 days after treatment compared to treatment with EPO, FN or vehicle.
Applicant argues that synergy is shown for example by the marked increase in wound healing on day 6 of the experiment (FIG. 6) when the percentage of healing attained was approximately 86% for mice treated with EPO and FN compared to mice treated with EPO (approximately 46%), mice treated with FN (approximately 41%) or control mice (approximately 30%).
Applicant maintains that the Office incorrectly states in the Office Action of the related application (US application 14/176,257, dated 14 June 2016), that, “an additive effect would be around 87%”. Applicant argues that such an assertion did not properly compare the improvements over the baseline wound closure for the individual ingredients as well as the combination so that the comparison is more accurate. Applicant argues that the additive effect should be calculated based on the activities when normalized to the baseline (e.g., control).
Applicant argues that EPO’s 46% + FN’s 41% = 87%, but EPO’s 46% closure includes the baseline wound closure of the wound, which would occur whether or not EPO was present. Applicant argues that the baseline for that time point of 30% (the control mice wound closure amount) and FN’s 41% also includes the same baseline wound closure of 30%. Applicant argues that the improvement provided by EPO is approximately 16% wound closure over the baseline (46% - 30% = 16%) and the improvement provided by FN is approximately 11% wound closure over the baseline (41% - 30% = 11%).
Applicant argues that to avoid counting the baseline twice to normalize the results, the calculation for an additive effect should include the sum of the improvements over the baseline for each ingredient and the baseline, so that the calculated additive wound closure would be a 57% wound closure (EPO 16% + FN 11% + control 30% = 57%) not 87% because that counts the baseline twice (16+30+11+30=87). Applicant argues that the measurement at day 6 for mice treated with both EPO and FN of 86% is 29% when properly normalized (86% - 57% = 29%).
Applicant argues that another way to look at the comparison is to compare just the improvements over baseline for all the results (zeroing the results to the baseline; control 30%). The improvement provided by EPO is approximately 16% wound closure (46%- 30%=16%), the improvement provided by FN is approximately 11% wound closure (41%-30% =11%), and the additive improvement would be 27% increased wound closure (16% + 11% = 27%). Applicant argues that the measured improvement provided by the combination of EPO and FN is approximately 56% wound closure (86% - 30% = 56%).
Applicant argues that this is a 29% wound closure, which is greater than the additive improvements of EPO and FN of 27% (56%-27%=29%). Applicant argues that this is just over a doubling of the improvement of the calculated additive effect (56/27=2.07).
Applicant continues to discuss the wound healing experiments in Example 2 (paras 0216-0237), microvascular density (paras 0238-0240), VEGF levels in wounds of treated and untreated mice (paras 0241-0242) and hydroxyproline experiments (paras 0243-0244), using the same calculations discussed above.
Applicant’s arguments have been fully considered but are not found persuasive for the following reasons:
1. The instant claims are not commensurate in scope with Applicant’s arguments regarding synergy and unexpected results.
The Examiner notes that Example 2 teaches a pharmaceutical composition comprising 3000 U/mL of EPO and 200 ug/mL of fibronectin, wherein the pharmaceutical composition is a cream.
However, the instant claims are drawn to a pharmaceutical composition comprising about 10-30 ug/mL of EPO and 100-300 ug/mL of fibronectin, wherein the pharmaceutical composition is a gel.
It is also noted that the unit (U)/international unit (IU) depends on the substance being measured. The specification teaches 3000 U/mL erythropoietin was purchased from Cytolab/Peprotech, Rehovot, Israel. There is no teaching of the conversion into ug/mL.
2. The instant specification employs the Walker formula to calculate the quantitative assessment of wound healing. The Kolmogorov-Smirnov test was employed for the statistical analysis. The instant specification teaches according to Kolmogorov-Smirnov test, the data had normal distribution. Student t-test and ANOVA were used to determine the differences between the different experimental groups. Differences were considered significant when P<0.05. Results were given as means of values ± standard deviation (para 0202).
Applicant makes calculations but does not cite any reference which teaches that in addition to the Walker formula, the Kolmogorov-Smirnov test, student t-test and ANOVA, wound closure values should be calculated using the formula discussed by Applicant.
MPEP § 716.01(c) II states: Arguments presented by Applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Examples of statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results…”.
3. The specification does not teach using the formula discussed by Applicant when calculating the fold compared between EPO+FN and the control vehicle. The instant application teaches the following:
“Hydroxyproline (HP) Analysis was used as an indicator of the amount of collagen present in the wound tissues. As depicted in FIG. 13, topical treatment with a cream containing only EPO or only FN equally enhanced HP content in the wounds tissue (44±6.1 or 45.3±7.2 μg/wound, respectively) and was significantly higher compared to treatment with vehicle (16.2±4.7 μg/wound, P<0.001). Conversely, topical treatment with a cream containing both EPO and FN significantly increased HP content in the wound tissue (81±8.8 μg/wound; P<0.001). Thus, by 2 folds compared to treatment with a cream containing only EPO or only FN and by 5 folds compared to treatment with vehicle” (paras 0243-0244).
A cream containing both EPO and FN that increased HP content in the wound tissue by 5 fold compared to treatment with vehicle would be 5 X 16.2 = 81. This is what the specification teaches for cream containing both EPO and FN (81±8.8 μg/wound; P<0.001). 81/16.2 = 5 (5 fold compared to vehicle).
The specification does not teach using the formula discussed by Applicant involving comparing the improvements over baseline for the results (zeroing the results to the baseline; control). This would be 81-16.2 =64.8; 64.8/16.2 = 4 (4 folds compared to vehicle), but the specification teaches 5 folds compared to vehicle.
4. MPEP 716.02(a) states: Evidence Must Show Unexpected Results [R-07.2022] I. GREATER THAN EXPECTED RESULTS ARE EVIDENCE OF NONOBVIOUSNESS:
"A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue." In re Corkill, 771 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). In Corkhill, the claimed combination showed an additive result when a diminished result would have been expected. This result was persuasive of nonobviousness even though the result was equal to that of one component alone. Evidence of a greater than expected result may also be shown by demonstrating an effect (which is greater than the sum of each of the effects taken separately (i.e., demonstrating "synergism"). Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). However, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) (Evidence showing greater than additive sweetness resulting from the claimed mixture of saccharin and L-aspartyl-L-phenylalanine was not sufficient to outweigh the evidence of obviousness because the teachings of the prior art lead to a general expectation of greater than additive sweetening effects when using mixtures of synthetic sweeteners.).
See Tallarida (cited herewith) who teaches that the determination of synergism is a quantitative pursuit that involves a rigorous demonstration that the combination effect is greater than that which is expected from the individual drug’s potencies. Tallarida teaches that that synergism is not merely a property of the 2 drugs. It also depends on the doses of each in the combination (dose equivalence). Tallarida teaches the method of isoboles. Tallarida teaches that this method is not a mechanistic approach; rather it is a method that uses the dose-effect data of the individual drugs. The potency and efficacy information derived from the individual dose-effect curves allow a determination of the expected combination effect or dose combination that produces a specified effect. Tallarida teaches that the expected effect (termed additive) is then statistically compared with the observed drug combination data, thereby indicating whether a departure from additivity such as synergism has occurred. Tallarida teaches that the analysis leading to the isobole is derived from dose-effect data of each compound. Tallarida teaches the method of isoboles is a graphical procedure, introduced and developed by Loewe (pages 1003-1005).
Tallarida teaches that although the method of isoboles is not based on explorations of mechanisms, the detection of a nonadditive interaction is an important first step in the further exploration of mechanism (R. J. Tallarida, “Drug synergism: its detection and applications. Journal of Pharmacology and Experimental Therapeutics, vol. 298, no. 3, pp. 865–872, 2011).
Regarding mechanisms, Ortiz et al. (cited herewith) teach that the purpose of combining two or more drugs with different mechanisms of action is to achieve a synergistic interaction, yielding a significant effect with lower doses, and therefore reducing the intensity and incidence of untoward effects. Ortiz et al. teach a study that illustrates the pharmacological and physiological mechanisms that justify the use of a combined drug therapy. The authors point out how a combination drug treatment strategy, wherein several pain related mechanisms are simultaneously engaged, may be more efficacious than treatment against individual mechanisms alone. This makes it possible to reduce the doses of the individual drugs, thereby minimizing the potential for adverse side-effects (Ortiz et al. Analgesic Drugs Combinations in the Treatment of Different Types of Pain. Pain Research and Treatment Volume 2012, Article ID 612519, 2 pages).
Based on Applicant’s arguments and the cited teachings (Tallarida and Ortiz), an unexpected synergistic effect of EPO and FN has not been established. The scientific reasoning and evidence as a whole indicates that the rejection should be maintained.
Claims 22 and 24 remain rejected under 35 U.S.C. 103 as being unpatentable over Ranby (US 2005/0187158; published 25 August 2005) in view of McCluskey et al. (Australian and New Zealand Journal of Ophthalmology. Vol. 15: 257-262; 1987) and Sultana et al. (Drug Delivery 13:215-219; 2006).
The basis for this rejection is set forth in the prior Office Action (13 December 2024, pages 11-13).
Applicant combines the arguments discussed above in the maintained rejection to claims 22, 23, 25 and 26 under pre-AlA 35 U.S.C. 103 as being unpatentable over Ranby in view of Powell, to the instant rejection.
Applicant’s arguments have been fully considered but are not found persuasive for the reasons discussed above and reasons of record. The scientific reasoning and evidence as a whole indicates that the rejection should be maintained.
Claims 22 and 27 remain rejected under 35 U.S.C. 103 as being unpatentable over Ranby (US 2005/0187158, published 25 August 2005) in view of in view of Horowitz et al. (U.S. Patent 5,514,647, published 07 May 1996) and Sultana et al. (Drug Delivery 13:215-219; 2006). The basis for this rejection is set forth in the prior Office Action (13 December 2024, pages 14-17).
Applicant combines the arguments discussed above in the maintained rejection to claims 22, 23, 25 and 26 under pre-AlA 35 U.S.C. 103 as being unpatentable over Ranby in view of Powell, to the instant rejection.
Applicant’s arguments have been fully considered but are not found persuasive for the reasons discussed above and reasons of record. The scientific reasoning and evidence as a whole indicates that the rejection should be maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ELIZABETH C. KEMMERER/ Primary Examiner, Art Unit 1674
/R.M.D/Examiner, Art Unit 1647 7/24/2025