DETAILED ACTION
The receipt is acknowledged of applicant’s amendment filed 03/04/2026.
Claims 1-15 previously presented. Claims 2 and 13 had been canceled. Claims 1, 3-12, 14-15 are pending.
Claim 15 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention II, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/07/2025.
Claims 1, 3-12, and 14 are subject of this office action.
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 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 7 is 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 7 is confusing because the claim requires the use of carboxymethyl cellulose, and exclude the use of cellulose gum that is carboxymethylcellulose. Both cellulose gum and carboxymethylcellulose are the same compound as evident below:
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Further, as evident above, CMC is used in its sodium salt, i.e. salt of cellulose gum, that is excluded from the claim.
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.
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, 3-12, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al. (US 2018/0271773, IDS filed 04/26/2023) as evidenced by the article by Woith et al. (“Extracellular vesicles-connecting kingdom”, previously cited on PTO 892 and copy is provided), and combined with the article by Antunes et al. (“The kinetics of small extracellular vesicle delivery impacts skin tissue regeneration”, previously cited on PTO 892, and copy has been provided), and further combined with Davis et al. (US 2008/0020070, currently cited on PTO 892), and Viegas et al. (US 6,136,334, previously cited on PTO 892).
Applicant Claims
Claim 1 is directed to a method of promoting angiogenesis and cell proliferation in a subject in need of tissue repair and/or regenerative therapy, said method comprising administering to the subject a pharmaceutical hydrogel composition providing a controlled release of orange-derived extracellular vesicles (EVs)over a period of at least 24 hours said composition comprising:
(i) orange-derived extracellular vesicles (EVs) purified from Citrus sinensis juice or Citrus sinensis plant cell cultures;
(ii) a single polymer gelling agent selected from carboxymethylcellulose, collagen, chitosan, gelatin, or hyaluronic acid;
(iii) water in an amount of at least 10% by weight of the total weight of the pharmaceutical composition; and
(iv) optionally, pharmaceutically acceptable vehicles, excipients, and/or diluents,
wherein the orange-derived extracellular vesicles (EVs) are enclosed by a lipid bilayer membrane have a diameter ranging from 10 to 500 nm as measured by light scattering-based nanoparticle tracking analysis (NTA), and show pro-angiogenic activity, and
wherein the polymer gelling agent and the water form a hydrogel matrix in which the orange-derived EVs are dispersed, said orange-derived EVs being releasable from the hydrogel matrix.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Lee teaches composition containing extracellular vesicles (EVs) derived from plant, wherein the extracellular vesicles have excellent effect on wound healing promotion effects, and improving skin conditions, e.g. cell proliferation in the wound site (abstract; ¶¶ 0008-0009, 0016, 0084, 0120, 0129). EVs are extracted from orange leaves of citrus fruit tree (¶¶ 0067, 0068). The EVs are present in the composition at a concentration of 5-10 µg/ml (¶ ¶ 0017, 0021, 0041, 0099, 0101). EVs have diameter between 30-1000 nm as measured by NTA (¶¶ 0065, 0108). The composition can be topical composition comprises excipients and diluents including gelatin (¶¶ 0071, 0078), claimed as gelling agent. The composition further comprises antibiotic, antibacterial, and antifungal agents (¶ 0079). EVs are naturally enclosed by lipid bilayer as evidenced by the article by Woith. Woith teaches EVs are shed from cell of almost every type cell or organism showing their ubiquity through all empires of life, including plants, e.g. orange. EVs are defined as naturally released particles from cells delimited by lipid bilayer and are loaded by RNA and protein and protect protein and RNA from degradation and deliver them to target tissue. (See entire Woith document, and in particular: abstract; pages 2, 4, 6, 14; and conclusion).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
While Lee teaches topical composition comprising EVs and gelatin and cellulose derivatives, e.g. methyl cellulose, the reference does not teach hydrogel composition and its ingredients as claimed by claim 1 including water. While Lee teaches EVs from plant including citrus plant, e.g. orange, the reference does not explicitly teach the claimed Citrus sinensis claimed by claim 1.
Antunes teaches EVs improves tissue regeneration at molecular, cellular, and tissue level. EVs have diameter of 50-200 nm. EVs are delivered topically in a hydrogel composition. EVs have the capacity to help regenerate chronic wound by re-epithelization and nano-vascularization. When hydrogel containing EVs is applied to skin, and the EVs are released overtime, the EVs provide a temporary extracellular matrix for cell infiltration and adhesion, and during hydrogel degradation, cells would infiltrate the space occupied by hydrogel and would be modulated by the release of EVs, and hydrogel will be replaced by cells that migrate from the proximity and proliferate. The hydrogel comprises hyaluronic acid (HA). The reference teaches HA hydrogel comprising 2 µg EVs improves closure of chronic wounds, e.g. diabetic ulcer. (See the entire document and in particular: abstract; pages 8695-8696, 8698, 8700, 8702-8703).
Davis teaches citrus fruit extract used for promoting angiogenesis or used for wound healing. The citrus fruit is extracted from mandarin, that is a Citrus sinensis. The extract is included in topical composition in the form of gel (see the entire document, and in particular abstract; ¶¶ 0012, 0013, 0017-0020).
Viegas teaches topical hydrogel useful for wound healing and for delivering active agent to injuries tissues, e.g. wound, and the hydrogel protects the skin and the wound from undesired adhesion, with or without medication. The hydrogel comprises 0.01-60% active agent, 1-50% gelling agent, and the rest water, that can be more than 10% of the composition based on the other components. The gelling agent is film forming polymers comprising HA, gelatin, collagen, and preferably carboxymethyl cellulose (CMC). The hydrogel can has pH of 7.0 or 6.88. The hydrogel comprises antibacterial substances and anti-inflammatory agents. (See the entire document, and in particular: abstract; col.4, lines 49-60; col.5, lines 1-17, 26-29; col.6, lines 26-42; col.7, lines 40-55; col.10, lines 16-39; claims 7-8; and examples).
Finding of Prima Facie Obviousness Rational and Motivation
(MPEP §2142-2143)
Therefore, it would have been obvious to one having ordinary skill in the art before the effective filing date of the present invention to provide topical composition comprising excellent wound healing comprising EVs derived from orange as taught by Lee, evidenced by Woith, and provide the EVs in a hydrogel composition comprising HA as taught by Antunes. One would have been motivated to do so because Antunes teaches topical hydrogel comprising EVs improves tissue regeneration at molecular, cellular and tissue level, and helps to regenerate chronic wound by re-epithelization and nano-vascularization when releases the EVs in the wound after degeneration of the hydrogel, and is capable to treat diabetic ulcer. One would reasonably expect treating chronic wounds including diabetic ulcer and improving tissue regeneration by using hydrogel comprising EVs from orange and HA.
Further, one having ordinary skill in the art would have been motivated to treat chronic wound and improve tissue regeneration by using hydrogel comprising EVs from orange and HA as taught by Lee, evidenced by Woith and combined with Antunes, and use EVs from mandarin which is Citrus sinensis as taught by Davis. One would have been motivated to do so because Davis teaches that citrus fruit extract from mandarin is useful for promoting angiogenesis in wound healing. One would reasonably and successfully expected to improve angiogenesis and wound healing using hydrogel composition comprising EVs from Citrus sinensis.
Furthermore, one having ordinary skill in the art would have use the hydrogel comprising EVs and HA taught by the combination of Lee evidenced by Woith and combined with and Antunes and Davis, and use the hydrogel taught by Viegas comprising HA and water because Antunes desired to use hydrogel comprising HA, and because Viegas teaches topical hydrogel comprising HA and water is useful for wound healing and for delivering active agent to injured tissues, and protect the skin and the wound from undesired adhesion, with or without medication.
Regarding EVs from orange plant as claimed by claim 1, Lee, evidenced by Woith, and combined with Davis teach EVs derived from Citrus sinensis plant.
Regarding the limitation of claim 1 that the EVs are enclosed in lipid bilayer, this is natural structure of all EVs as evidenced by Woith that teaches all EVs shed from every type of cells show their ubiquity through all empires of life, including plants, e.g. orange, and all EVs are defined as naturally released particles from cells delimited by lipid bilayer.
Regarding the diameter of EVs as claimed by claim 1 of 10-500 mm, Lee teaches 30-1000 nm that overlaps with the claimed diameter, and Antunes teaches 50-200 nm that falls within the claimed diameter. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05 [R-5].
Regarding release of EVs from the hydrogel as claimed by claim 1, this is taught by Antunes.
Regarding the limitation of single polymer gelling agent selected from carboxymethyl cellulose (CMC), collagen, chitosan gelatin or hyaluronic acid as claimed by claim 1, Antunes teaches single hydrogel polymer hyaluronic acid and Viegas teaches list of polymers selected from the group consisting of “….hyaluronic acid…” (see claim 7); and preferred film forming polymer is CMC (claim 8 and col.6, lines 40-41). This teaching implies single film forming polymer.
Regarding the release of EVs from the hydrogel for at least 1 day claimed by claims 1, the cited references teaches the same claimed hydrogel comprising the claimed EVs, and period of release of EVs from the hydrogel of the prior art is expected to be the same as claimed, absent evidence to the contrary.
Regarding the limitation of “measuring the diameter of the EVs by NTA”, this is taught by Lee. It is noted that the process of measuring the particle size is not part of claimed method of “promoting angiogenesis… or regeneration therapy…”, and it does not impart patentability to the claims.
Regarding claim 1 that the orange derives EVs are derived from Citrus sinensis plant, mandarin taught Davis is species of Citrus sinensis.
Regarding claim 3 the volume of EVs per ml as claimed by claim 3, one having ordinary skill in the art would have determined such volume in the light of the teaching of the prior art regarding the size of EVs and the desired use and pharmaceutical effect.
Regarding amount of EVs in the composition of 5-500 ug/ml as claimed by claim 4, Lee teaches 5-10 µg/ml that falls within the claimed amount. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05 [R-5].
Regarding protein content and RNA content of the EVs as claimed by claims 5 and 6, respectively, EVs are naturally loaded with these ingredients as evidenced by the Woith, and the content of each ingredient would be the same in orange claimed by applicant and taught by the cited references. .
Regarding gelling agents as claimed by claim 7, Antunes teaches HA and Viegas teaches gelling agent selected from HA, gelatin, collagen, carboxymethyl cellulose. Therefore, the references suggest single polymer, and suggest exclusion of others. Not all the polymers to be used together. Note that Viegas claim 8 is directed to CMC that exclude other polymers.
Regarding therapeutic agents claimed by claim 8, Lee teaches antibacterial agents and Viegas teaches antibacterial and anti-inflammatory agents.
Regarding the pH claimed by claim 9, Viegas teaches pH of 7 and 6.88 that falls within the claimed pH. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05 [R-5]. However, one having ordinary skill in the art would have determined the pH of the hydrogel based on the condition to be treated.
Regarding the limitation “tissue repair is for closing a tissue lesion” as claimed by claim 10, all the cited references teach wound healing, i.e. wound closing.
Regarding diseases claimed by claim 11, all the cited references teach wound healing effect, Antunes teaches diabetic ulcer treatment.
Regarding topical administration as claimed by claim 12, all the cited references teach topical administration.
Regarding the release of EVs from the hydrogel for at least 7 days as claimed by claims 14, the cited references teaches the same claimed hydrogel comprising the claimed EVs, and period of release of EVs from the hydrogel of the prior art is expected to be the same as claimed, absent evidence to the contrary.
Absent any evidence to the contrary, and based upon the teachings of the prior art, there would have been a reasonable expectation of success in practicing the instantly claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present invention.
Response to Arguments
Applicant's arguments filed 03/04//2026 have been fully considered but they are not persuasive.
Rejections under 35 U.S.C. § 112
Applicants argue that claim 7 is amended consistent with the comments of the Office.
In response to this argument, it is argued that the claim as amended recites cellulose gum and sodium carboxymethylcellulose that are the same compound as evident by:
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Further, the amended claim is confusing because it requires CMC that is cellulose gum, and meanwhile the claim excludes cellulose gum.
Rejections under 35 U.S.C. § 103
A) Lee does not teach or suggest pro-angiogenic activity of orange-derived EVs.
Applicants argue that Lee neither discloses nor suggests any pro-angiogenic activity, nor does Lee teach treatment or healing of ischemic or chronic wounds. Instead, Lee is directed to cosmetic applications, such as wrinkle reduction and general skin conditioning. By contrast, the present application demonstrates that orange-derived EVs obtained from Citrus sinensis fruit exhibit clear pro-angiogenic biological activity, including enhanced endothelial tube formation and endothelial cell migration, as shown in FIGS. 4-7 of Applicant's published application. Lee does not provide any teaching or suggestion that plant-derived EVs, let alone EVs derived from Citrus sinensis fruit, would promote angiogenesis or wound regeneration. Nor does Lee provide any motivation for a person of ordinary skill in the art to combine its cosmetic EV compositions with hydrogels for the purpose of promoting angiogenesis and treating wounds.
In response to this argument, it is argued that the current claims recite: “….promote angiogenesis and cell proliferation ….tissue repair/regenerative therapy…”, and Lee clearly teaches use of plant EVs and suggests citrus fruits from orange for cell proliferation in the wound site in paragraph [0084], and keratinocyte cell proliferation in paragraphs [0120] and [0129]. Therefore, unlike applicants assertion, Lee teaches cell proliferation as claimed. Further, Lee does not teach only treatment of wrinkles, but further teaches wound healing and cell proliferation as claimed, and suggests citrus fruits in paragraph [0067] and claim 19. The specifically claimed citrus fruit is taught by the secondary references. If Lee was to teach the claimed Citrus sinensis, the reference would have been considered for anticipation specially Lee teaches the claimed gelatin that is claimed by applicants as hydrogel. One cannot attack the references individually wherein obviousness is based on combination of the references. Motivation to use Citrus sinensis is provided by the secondary references, as set forth in this office action.
Any property applicants achieved from the present invention would be expected from the composition taught by combination of the cited references, e.g. orange-derived EVs obtained from Citrus sinensis fruit would exhibit what applicants achieved. This is because, the combination of the cited references teaches all the elements of the claimed method.
B) Antunes does not relate to plant derived EVs and provides no motivation for the claimed combination.
Applicants argue that Antunes does not disclose or suggest EVs derived from Citrus sinensis. Mammalian EVs differ substantially from plant-derived EVs in their structure, biological content, stability, and interactions with tissues. These cross-kingdom differences are indeed recognized in Woith, which explains that EVs from different biological kingdoms exhibit markedly different properties and behaviors. that Antunes does not teach or suggest that encapsulating EVs in a hydrogel would increase their biological activity over time. Antunes also fails to disclose or suggest a time-dependent enhancement of biological effect, protection of EVs from degradation, or synergistic interactions between EVs and the hydrogel matrix.
In response to this argument, it is argued that Antunes is relied upon for teaching topical hydrogel comprising EVs, regardless the source of EVs, and HA improves tissue regeneration at molecular, cellular and tissue level, and helps to regenerate chronic wound by re-epithelization and nano-vascularization when releases the EVs in the wound after degeneration of the hydrogel, and is capable to treat diabetic ulcer. EVs of citrus plant origin e.g. orange, is taught by Lee, and specific species of Citrus sinensis is taught by Davis. In any event, all EVs are shed from cells of almost every type of cell or organism as evidenced by Woith. Increasing the biological activity of encapsuled EVs is an expected property from the encapsulated EVs in HA taught by combination of Lee with Antunes.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., encapsulated EVs, a time-dependent enhancement of biological effect, protection of EVs from degradation, or synergistic interactions between EVs and the hydrogel matrix) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In any event, any properties applicants achieved are expected from the prior art in combination that teaches the claimed method using the claimed product, absent evidence to the contrary.
Applicants argue that the cited references do not provide any teaching or suggestion that the claimed combination would achieve the biological effects demonstrated in the present application. The Office has not established that a person of ordinary skill in the art would have had any reasonable expectation of success in arriving at the claimed invention based on the disclosures of Lee, Woith, and/or Antunes. Therefore, the combination is not prima facie obvious.
In response to this argument, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, motivation to combine the cited references exists even if motivation is different from what applicants had done, and reasonable expectation to achieve the present invention was presented, as set forth in this office action. Obviousness does not require absolute predictability, only reasonable expectation of success, and references are evaluated by what they suggest to one versed in the art rather by their own specific disclosure. The claimed method would have been prima facie obvious in view of combination of the cited references, as set forth in this office action.
C) No reference suggests controlled, prolonged release (≥24-72 hours).
Applicants argue that Viegas merely discloses generic hydrogel systems and does not describe hydrogels designed to preserve EV cargo or to provide a controlled EV delivery profile over at least 24-72 hours. In contrast, Applicant demonstrates in FIG. 2 of the published application that orange- derived EVs from Citrus sinensis are preserved within the hydrogel matrix and released gradually over a period of at least 72 hours (i.e., "at least 24 hours," as recited in amended claim 1). This controlled release directly enables the unexpected biological synergy described in the present application. The combination of cited references fails to teach or suggest the structural and functional features that are reflected in the present claims.
In response to this argument, as applicants themselves noticed, Viegas is relied upon for solely teaching the claimed hydrogel. If Viegas was to teach hydrogels designed to preserve EV cargo or to provide a controlled EV delivery profile over at least 24-72 hours, the reference would have considered for anticipation. The refence satisfied the purpose for which it was applied. Combination of the cited references teaches the claimed method comprising the claimed steps and ingredients used, and any properties applicants achieved, e.g. synergy, controlled release, etc., are expected from combination of the cited references, absent evidence to the contrary. Note that controlled release of EVs contained in HA hydrogel is suggested by Antunes.
D) Unexpected and synergistic results rebut prima facie obviousness.
Applicants argue that across FIGS. 3-9 of the published application, the inventors demonstrate strong, statistically significant, and unexpected results. First, the data show a time-dependent enhancement of cellular uptake. EVs administered alone exhibit declining uptake after approximately 24 hours. In contrast, EVs encapsulated within the hydrogel exhibit substantially increased cellular uptake after 48-72 hours. This represents an unexpected reversal of the trend observed for EVs alone and indicates that the hydrogel delivery system fundamentally alters EV behavior over time. Second, the results demonstrate a strong synergistic enhancement of angiogenesis. The EV- hydrogel compositions produce significantly greater endothelial tube formation than either EVs alone or hydrogel alone. The magnitude of the angiogenic response exceeds what would be expected from the individual components, demonstrating a synergistic effect. None of the cited references (nor any combination thereof) teaches or suggests such synergy. Third, the data show accelerated wound closure in vivo, including in both normal wounds and diabetic ulcer models. The EV-hydrogel compositions significantly accelerate wound closure as early as three days after treatment. This effect is particularly notable in diabetic models, which are well known to exhibit severely impaired healing. The cited references (nor any combination thereof) do not predict or suggest such a dramatic therapeutic improvement.
Regarding applicant's arguments of unexpected superior results in the instant specification, it is argued that the data in the specification are not unexpected results and therefore cannot rebut prima facie obviousness. The examiner directs applicant's attention to MPEP 716.02 (a). "A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness...of the claims at issue." In re Corkhill, 711 F.2d 1496, 266 USPQ 1006 (Fed.Cir. 1985). In Corkhill, the claimed combination showed an additive result when a diminished result would have been expected. Furthermore, the MPEP states, "Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967).
First, the data regarding a time-dependent enhancement of cellular uptake of EVs encapsulated in hydrogel that increased cellular uptake after 48-72 hours versus administering EVs alone that exhibit declining uptake after approximately 24 hours, it is noted that applicants data does not commensurate in scope with the claims because claim 1 and dependent claims do not recite encapsulating EVs in the hydrogel, rather the claims recite only composition comprising both EVs and hydrogel. Further, it is noted that the features upon which applicant relies (i.e., encapsulated EVs in the hydrogel) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Second, regarding synergism, it is noted that the claimed method and composition comprising both EVs and hydrogel, are taught by the cited references in combination. MPEP 716.02(a) states, “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)”. “There is no single, appropriate test for determining whether synergism has been demonstrated for chemical combination; rather, facts shown in each case must be analyzed to determine whether chosen method has clearly and convincingly demonstrated existence of synergism or unobvious result”. “Assuming arguendo that the differences in values presented are statistically significant, there is no evidence that they represent a true, practical advantage. In re Freeman, 474 F.2d 1318, 177 USPQ 139 (CCPA 1973); In re Klosak , 455 F.2d 1077, 173 USPQ 14 (CCPA 1972); In re D'Ancicco, 439 F.2d 1244, 169 USPQ 303 (CCPA 1971). Also, prescinding from the Colby formula test, which as we have already indicated is at best controversial and in our view probably invalid, there is no evidence that the differences are unexpected. In re Merck, 800 F.2d 1091, 231 USPQ 375 (Fed.Cir. 1986); In re Longi , 759 F.2d 887, 225 USPQ 645 (Fed.Cir. 1985); In re Freeman, supra” .
Third, the data of accelerated wound closure in vivo, including in both normal wounds and diabetic ulcer models, are expected from the prior art as discussed above. At least Lee and Davis references teach promoting wound healing.
It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose in order to form a third composition that is to be used for the very same purpose; the idea of combining them flows logically from their having been individually taught in the prior art. In re Kerkhoven, 205 USPQ 1069.
Applicants argue that the synergistic and time-dependent biological enhancements demonstrated in the present application were neither predictable nor suggested by the cited references Lee, Woith, Antunes, and/or Viegas, and therefore weigh strongly against a conclusion of obviousness.
In response to this argument, the argument regarding synergism and unexpected result in the specification are hereby reiterated as above. Obviousness does not require absolute predictability of success all that is required is a reasonable expectation of success. See In re Kubin, 561 F.3d at 1360. The Court has held that "the test of obviousness is not express suggestion of the claimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them." See In re Rosselet, 146 USPQ 183, 186 (CCPA 1965). "There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art." Motorola, Inc. V. Interdigital Tech. Corp., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997). An obviousness determination is not the result of a rigid formula disassociated from the consideration of the facts of a case. Indeed, the common sense of those skilled in the art demonstrates why some combinations would have been obvious where others would not. See KSR Int'l Co. V. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) ("The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.").
E) Pro-angiogenic activity is not inherent or suggested by the prior art
Applicants argue that Woith does not attribute any pro-angiogenic properties to EVs derived from Citrus sinensis or from plant sources generally. Rather, Woith merely explains that extracellular vesicles across different biological kingdoms share certain basic structural characteristics, such as the presence of lipid bilayer membranes. Woith does not suggest that plant-derived EVs, or specifically EVs from orange (Citrus sinensis), would exhibit therapeutically meaningful angiogenic activity as shown by applicants.
In response to this argument, it is argued that Woith is an evidentiary reference relied upon for solely teaching that EVs are naturally enclosed by lipid bilayer, Woith teaches EVs are shed from cell of almost every type cell or organism showing their ubiquity through all empires of life, including plants, e.g. orange. EVs are defined as naturally released particles from cells delimited by lipid bilayer and are loaded by RNA and protein and protect protein and RNA from degradation and deliver them to target tissue. The reference does not need to teach any of the features of the claims, and the reference satisfies the purpose for which it was applied.
F) The Office's proposed combination relies on hindsight.
Applicants argue that the Office's rejection relies on the combination of four disparate references, each directed to different types of EVs, different therapeutic objectives, and different formulation technologies. Such a reconstruction requires impermissible hindsight. The cited prior art provides no teaching or motivation to combine EVs derived from Citrus sinensis fruit with hydrogel matrices to achieve improved angiogenesis, enhanced cell proliferation, or accelerated wound healing through a controlled release mechanism.
In response to this argument, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case the examiner relied on the teaching of the cited references to construe the rejection, and not on applicant’s disclosure. All the elements of the claims are taught by combination of the cited references. Further, motivation to combine the references exists, and reasonable expectation to achieve the present invention, as s et forth in this office action. The four cited references are analogous art, and are in the field of the inventor’s endeavor, and are reasonably pertinent to the particular problem with which the inventor was concerned, using EVs in skin regeneration. Therefore, it is proper to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992).
Double Patenting
Applicants argue that the claims of the '020 Application do not require a hydrogel, controlled release, synergistic biological enhancement, or any of the functional characteristics recited in the present claims.
This argument is moot in view of withdrawing the rejection based on abandonment of application ‘020.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Isis A D Ghali whose telephone number is (571)272-0595. The examiner can normally be reached Monday through Friday, 8:30 AM to 5:00 PM EST.
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/ISIS A GHALI/Primary Examiner, Art Unit 1611 /I.G./
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