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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 4/3/2026 has been entered.
Response to Arguments
Applicant’s response from 4/2/2026 is acknowledged.
Claim Rejections - 35 USC § 103
Applicant has made arguments over the claims as amended. In view of Applicant’s claim amendments a modified rejection has been made below.
Double patenting
Applicant has asked that the rejections be held in abeyance. Accordingly, the rejections are restated for the record.
Claims 1, 3-5, 17 and 19-24 are pending, and have been examined herewith.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 3-5, 17 and 19-24 are rejected under 35 U.S.C. 103 as being unpatentable over US 20120302645 A1 to Liu et al. (“Liu”, of record), and further in view of CN 106213492A to Liu et al. (“Liu 2”; English translation referenced for citations, of record), Fujiwara et al., Oleuropein improves insulin resistance in skeletal muscle by promoting the translocation of GLUT4, J Clin Biochem Nutr. 2017 Nov;61(3):196-202 (“Fujiwara”, of record), and CA 3224027 A1 to Horcajada et al. (“Horcajada”).
Liu is directed to a method of maintaining or increasing muscle differentiation or regeneration after strenuous physical exercise or under conditions where muscle is chronically inflamed, comprising administering an effective amount of hydroxytyrosol (HT) to a mammal, and observing a muscle differentiation effect. (claim 1). Liu specifically discloses that: “[0016] In further embodiments of the present invention, hydroxytyrosol derivatives such as esters and physiologically/pharmaceutically acceptable salts may be used instead of or in addition to hydroxytyrosol. It is also possible to use a mixture of hydroxytyrosol and hydroxytyrosol derivatives. Derivatives can be e.g. esters or glucosides, and are known to the person skilled in the art. Preferred esters of hydroxytyrosol are e.g. acetates or glucuronide conjugates; as well as oleuropein being the most preferred one.” (emphasis added).
Thus, even though Applicant has amended claim 1 to recite “wherein the composition does not comprise hydroxytyrosol”, and has argued that removing hydroxytyrosol from the claim would change the principle of operation of Liu, this is clearly not the case. Support for this position is found in paragraph [0016] in the paragraph in the sections with bold and underlining. Thus, the language of the amendment clearly does not remove the disclosure on hydroxytyrosol as relevant. Stated simply, Liu makes explicit that the principle of operation of hydroxytyrosol and oleuropein is interchangeable, and that one may be used instead of the other.
Per Liu, “[0024] When used, hydroxytyrosol has the following benefits: [0025] helps improve effectiveness of your training regimen [0026] helps prevent symptoms of overtraining, [0027] helps reduce delayed onset muscle soreness (DOMS), [0028] helps improve your training outcome after strenuous exercise, [0029] helps your body adapt to exercise better, [0030] helps you to be able to train harder, [0031] helps you reduce the risk to overtrain, [0032] helps improve muscle regeneration after exercise especially strenuous exercise, [0033] helps improve muscle growth after exercise, especially strenuous exercise, [0034] helps muscle regeneration in aching muscles, [0035] supports muscle growth after strenuous exercise, [0036] supports muscle maintenance in elderly, [0037] supports muscle maintenance in Duchenne muscle dystrophy, [0038] supports muscle maintenance in inflammatory muscle wasting conditions.” Per Applicant’s claim 2, the above relate at least to skeletal muscle. Per Applicant’s claim 6, the exercise includes resistance exercise, etc. ([0005]).
The Examiner further notes at least the following relevant sections of Liu: “The pharmaceutical and nutraceutical compositions comprising hydroxytyrosol useful for conditions characterized by altered muscle differentiation especially under inflammatory conditions, such as delayed onset muscle soreness subsequent to strenuous exercise or sarcopenia are provided.” (Abstract). “[0001] This invention is related to the use of hydroxytyrosol ("HT"), or an olive juice extract containing hydroxytyrosol as an agent to improve muscle differentiation and thus improve or maintain the body's adaptation to exercise. It also relates to pharmaceutical and nutraceutical compositions useful for conditions characterized by altered muscle differentiation especially under inflammatory conditions, such as delayed onset muscle soreness subsequent to strenuous exercise or sarcopenia.”
[0004] Muscle differentiation is required for maintenance of the skeletal musculature, for wound healing after surgery, trauma or strenuous exercise. Moreover, the formation of new muscle fibers (myotubes) is required for muscle growth.
[0005] Improving or maintaining muscle differentiation is needed e.g. for adaptation to exercise, especially to resistance exercise, and thus is important for sports performance. Muscle differentiation is also needed for mobility and all associated aspects of health, ability to work, and to lead an active life style.
[0006] Improved muscle differentiation is a particular need of elite athletes, whose professional success depends on an optimized training regimen to be able to perform at top level at times of important competitions. Moreover, healthy muscle differentiation is of interest for life style athletes (recreationally active people, weekend warriors), who harness important experiences of fun and satisfaction from successful exercise performance. Women, who in general have a lower muscle mass than men, often are concerned about their physical capabilities, hence are in need of good muscle differentiation.
[0007] A successful training regimen strives to optimize adaptation of the body to exercise. Adaptation to exercise among others includes an increase in aerobic exercise capacity, increased lipid storage especially in oxidative muscle fibers, activation of the endogenous antioxidant defense system, increased vascularization of the musculature, increased erythropoiesis, synthesis of contractile fibers within muscle cells such as actin and myosin and others, and the recruitment of satellite cells to differentiate and fuse into myotubes.
[0008] Oxidative stress induced by exercise is thought to be causally involved in inducing adaptation to exercise, i.e. successful training. The reactive oxygen species are generated during muscle contractions, but also during aerobic energy metabolism (oxidative phosphorylation, oxphos, aerobic respiration). The redox-sensitive MAPK and NFkB signaling pathways and the resulting reactions of cellular stress and inflammation are regarded as important pathways mediating adaptation to exercise (reviewed in Li Li Ji, Free Radical Biology & Medicine 44 (2008), 142-152, Li Li Ji Exp Gerontology 42 (2007), 582-593). In line with this, intervention studies with the antioxidants allopurinol and vitamin C in animal models and in humans have found that antioxidant supplementation reduced adaptation to exercise (Gomez-Carbrera et al. 2005 J Physiol 567, 113-120, Gomez-Carbrera et al. 2008 Am. J. Clin. Nutr. 87(1):142-149, Ristow et al (2009) PNAS 106, 8665-8670).
([0004]- [0008]; emphasis added).
As an additional example showing teaching improving of muscle fatigue or weakness from exercise in Liu, the Examiner notes the endurance exercise procedure experiment in rats.
Endurance Exercise Procedure
[0085] Rats were randomly divided into four groups: Sedentary, Sedentary with HT supplement (25 mg/kg/day), Endurance exercise and Endurance exercise with HT supplement (25 mg/kg/day). HT was administrated by gavage 45 min before exercise program for each animal. Rats were run on a motorized treadmill at a speed of 20 m/min and a grade of 5.degree. for 1 hour per day and 6 days per week. After 8 weeks exercise, endurance capacity was measured by treadmill running to exhaustion at a speed of 30 m/min and a grade of 5.degree.. Exhaustion was defined as the inability to maintain running and avoid sound and light irritation.
Isolation of Skeletal Muscle Mitochondria
[0086] The soleus muscle was removed from each leg. A first portion was frozen in liquid N.sub.2 and used for total RNA and protein extraction. A second portion was used immediately for mitochondrial isolation. Soleus muscles were trimmed off fat and connective tissue, chopped finely with a pair of scissors, and used for mitochondrial isolation.
[. . .]
LTE (Long Term Exercise) on Endurance Capacity and Muscle Atrophy and the Effect of HT Supplement
[0092] We performed a LTE program with rats and studied the effects of HT supplement on physical performance and the underlying mechanism of mitochondrial dynamics. We showed that LTE was prone to reduce endurance capacity, and HT supplement was sufficient to improve endurance capacity of exercise rats by 35% without any effect on sedentary rats (FIG. 9A).”
Accordingly, Liu discloses Applicant’s claimed method. As the Federal Circuit holds, the elements must be arranged as required by the claim, but this is not an ipsissimis verbis test, i.e., identity of terminology is not required. In re Bond, 910 F.2d 831, 15 USPQ2d 1566 (Fed. Cir. 1990). See also MPEP 2131.
Per Liu, administration may be as a “dietary supplement”, which denotes a product taken by mouth that contains a compound or mixture of compounds intended to supplement the diet. The compound or mixture of compounds in these products may include, e.g. minerals. ([0062]). Although Liu does not specifically disclose calcium, it is noted that the term mineral, to include in a dietary supplement, is understood to include calcium. Liu further discloses that the nutraceutical compositions according to the present invention may be in any form that is suitable for administrating to the animal body including the human body, especially in any form that is conventional for oral administration, e.g. in solid form such as (additives/supplements for) food or feed, food or feed premix, tablets, pills, granules, dragees, capsules, and effervescent formulations such as powders and tablets, or in liquid form such as solutions, emulsions or suspensions as e.g. beverages, pastes and oily suspensions, and may comprise other ingredients, e.g. sugar, fat, etc. ([0063]). Liu further discloses administering every day for 1 month, and a sports supplement with a daily dose (Example 3).
Liu 2 teaches compositions and their administration to improve bone quality and increase muscle performance/ functionality as desirable combination formulations (see paragraph 6). The composition includes calcium, chondroitin sulfate, glucosamine hydroxide, and an oligopeptide to improve muscle performance. ([0008], [0023-27]). Liu 2 envisions oral administration of the composition, given its categorization of the product as a health food and description of a test subject taking the composition with/ for breakfast. ([0002], [0077]). Liu 2 specifically discloses calcium supplementation alone as far an active ingredient is concerned. ([0006])
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer a combination composition to a subject to improve resistance to muscle fatigue from exercise, as detailed by Liu where the oleuropein or its metabolite hydroxytyrosol composition is administered in combination with calcium, as taught by Liu 2. The skilled artisan would have been motivated to do so guided by the desire to as also improve with the addition of calcium bone quality while simultaneously increasing muscle performance/ functionality as taught by Liu 2. This modification would have been obvious as the application of the same technique to a similar product/method in order to yield the same improvement. Further motivation to do so is because both ingredients are further known food composition ingredients, and susceptible to co-formulation together as a nutraceutical composition or a dietary composition.
Applicant’s claim 19 recites “wherein the composition consists essentially of the calcium and the at least one of oleuropein or metabolite thereof.” The transitional phrase “consisting essentially of” limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention. In re Herz, 537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976). For the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, “consisting essentially of” will be construed as equivalent to “comprising.” See, e.g., See, e.g., PPG Indus. v. Guardian Indus. Corp., 156 F.3d 1351, 1355 (Fed. Cir. 1998). If an applicant contends that additional steps or materials in the prior art are excluded by the recitation of “consisting essentially of,” applicant has the burden of showing that the introduction of additional steps or components would materially change the characteristics of applicant’s invention. In re De Lajarte, 337 F.2d 870, 143 USPQ 256 (CCPA 1964). See also Ex parte Hoffman, 12 USPQ2d 1061, 1063-64 (Bd.Pat. App. & Inter. 1989). MPEP 2111.03. Since Applicant has not made a representation on the record that the transitional phrase “consisting essentially of” limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention, then under MPEP 2111.03 the transitional phrase “consisting essentially of” will be construed as equivalent to “comprising.”
But even if Applicant had made such a representation, as the office action established Liu teaches administering hydroxytyrosol (HT) alone in a method of maintaining or increasing muscle differentiation or regeneration after strenuous physical exercise or under conditions where muscle is chronically inflamed. (claim 1). Further, Liu 2 teaches supplementation with calcium alone as far an active ingredient is concerned. ([0006]). Accordingly, it would have been obvious to a person of skill in the art before the effective filing date of the claimed invention to combine the teachings of Liu and Liu 2, wherein the composition consists essentially of the calcium and the at least one of oleuropein or metabolite thereof, since both active ingredients have been individually shown in the art to be active for improving bone quality and increase muscle performance/ functionality.
Applicant’s claim 1, as amended, and new claims 23 and 24, broadly recite administering the oleuropein dose relative to the time of exercise. The Examiner points to at least the following relevant sections of Liu, which disclose optimizing the training regimen, and with it the means of administration, to include with respect to considerations such as whether it is in a subject in need of strenuous exercise, or an elite athlete, or for adaption to exercise, or for increasing aerobic capacity, etc.
[0004] Muscle differentiation is required for maintenance of the skeletal musculature, for wound healing after surgery, trauma or strenuous exercise. Moreover, the formation of new muscle fibers (myotubes) is required for muscle growth.
[0005] Improving or maintaining muscle differentiation is needed e.g. for adaptation to exercise, especially to resistance exercise, and thus is important for sports performance. Muscle differentiation is also needed for mobility and all associated aspects of health, ability to work, and to lead an active life style.
[0006] Improved muscle differentiation is a particular need of elite athletes, whose professional success depends on an optimized training regimen to be able to perform at top level at times of important competitions. Moreover, healthy muscle differentiation is of interest for life style athletes (recreationally active people, weekend warriors), who harness important experiences of fun and satisfaction from successful exercise performance. Women, who in general have a lower muscle mass than men, often are concerned about their physical capabilities, hence are in need of good muscle differentiation.
[0007] A successful training regimen strives to optimize adaptation of the body to exercise. Adaptation to exercise among others includes an increase in aerobic exercise capacity, increased lipid storage especially in oxidative muscle fibers, activation of the endogenous antioxidant defense system, increased vascularization of the musculature, increased erythropoiesis, synthesis of contractile fibers within muscle cells such as actin and myosin and others, and the recruitment of satellite cells to differentiate and fuse into myotubes.
[0008] Oxidative stress induced by exercise is thought to be causally involved in inducing adaptation to exercise, i.e. successful training.
([0004]- [0008]; emphasis added).
Accordingly, it would have been obvious to a person of skill in the art before the effective filing date of the claimed invention to optimize the time period of exercise, its intensity and duration relative to the administration of oleuropein or a metabolite thereof, as per Applicant’s claims, based on the disclosure of Liu. The skilled artisan would have been motivated to do so since Liu specifically discloses optimizing the exercise regimen taking into account various specifically enumerated considerations, and further in view of the need to intake a dietary supplement comprising oleuropein or a metabolite thereof so as to further optimize the process of muscle differentiation.
Timing of administration impacts drug pharmacokinetics, and is therefore a result- effective variable, which is subject to optimization. See MPEP 2144.05.
B.There is a Motivation to Optimize Result-Effective Variables
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process.
Therefore, a prima facie case of obviousness has been properly made. Applicant has failed to rebut it, with either argument, or data. For instance, there is nothing of record to show any criticality of Applicant’s claimed timing of administration. There is a sole paragraph in Applicant’s specification, devoid of any further data whatsoever, which simply just generally states that administering close to the time of exercise is selected.
“[0006] In an embodiment, the at least one of oleuropein or metabolite thereof is administered in at least one dose during at least one time period selected from the group consisting of (i) a pre-exercise time between one hour prior to initiation of the exercise and one second prior to the initiation of the exercise, such as between thirty minutes prior to the initiation of the exercise and one minute prior to the initiation of the exercise, (ii) an exercise time between the initiation of the exercise to conclusion of the exercise, and (i) a post-exercise time between one second after the conclusion of the exercise and one hour after the conclusion of the exercise, such as between one minute after the conclusion of the exercise and thirty minutes after the conclusion of the exercise.”
It is noted that administering an energy supplement close to the time when energy is needed is indeed obvious and subject to optimization. Generally, it is not inventive to discover such regimens by routine experimentation when the general conditions of a claim are disclosed in the prior art. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) and MPEP §2144.05(11). The medical arts recognize that drug therapy may be optimized by designing regimens that account for the concentration of a drug, for example, to achieve a desired pharmacological response. The factual underpinnings for doing so are further found in references of record, as well as supported by well-established precedent on optimization.
As discussed already vis-a-vis Liu, it specifically discloses skeletal muscle, which one of skill would know to include the specific skeletal muscles of Applicant’s claim 17. Fujiwara discloses that oleuropein improves insulin resistance in skeletal muscle by promoting the translocation of GLUT4. (Title). It specifically discloses testing its effect on the gastrocnemius muscles of mice. (Abstract). Fujiwara also reports that “Oleuropein is known to partially metabolize to tyrosol and hydroxyltyrosol.(38) These metabolites possess stronger anti-oxidative activity than oleuropein.(39)”.
Liu does not specifically disclose the addition of a protein source, such as whey protein.
Horcajada teaches increasing and improving muscle functionality (e.g. muscle strength, gait speed, etc.), reducing a loss of muscle functionality (e.g. muscle strength, gait speed, etc.), and improving recovery of muscle functionality after muscle atrophy or injury, in an individual in need thereof, by administering a composition with a therapeutically effective amount of oleuropein. (claim 10, [0057], [0090]). This disclosure is tantamount to improvement in muscle fatigue or weakness, and of physical energy. Muscles impacted by the method are preferably skeletal muscle. ([0059]). Horcajada teaches daily administration for at least one week ([0082]). Oral administration is the preferred administration route. ([0085]). Per Horcajada, the composition is selected from the group consisting of food compositions, dietary supplements, nutritional compositions, nutraceuticals, powdered nutritional products to be reconstituted in water or milk before consumption, food additives, medicaments, drinks, and combinations thereof. ([0019], claim 11). Horcajada teaches wherein the composition comprises a fatty acid and a protein source. (claims 2-5, 7). The protein source can comprise a protein selected from the group consisting of whey protein, casein, pea protein, soy protein and combinations thereof. ([0011]).
Horcajada further discloses Applicant’s claimed amount of new claim 20. “The one or more polyphenols may each be present in amount of from 0,01 mg to about 1 g, preferably from 0,1 mg to 1 g, even more preferably from 1 mg to about 1 g per serving.” ([0065]).
Horcajada does not explicitly teach that the composition further comprises calcium, but as discussed above does teach that the composition to be provided in milk (beverage) for consumption, and milk is a well-known source of calcium. This is further evidenced by Chaney. Chaney teaches that the normal mineral content of milk contains 125 mg calcium per 100 ml (see column 1 lines 24-34 including table).
Horcajada discloses improving muscle functionality (e.g. muscle strength, gait speed, etc.), reducing a loss of muscle functionality (e.g. muscle strength, gait speed, etc.), and improving recovery of muscle functionality after muscle atrophy or injury, which descriptive is broadly inclusive of preventing or treating muscle fatigue from exercise, and of improving resistance to muscle fatigue from exercise, but does not explicitly use the word “exercise”.
Accordingly, it would have been obvious to a person of skill in the art before the effective filing date of the claimed invention to combine the teachings of Liu, Liu 2, Fujiwara and Horcajada in order to practice Applicant’s claimed invention with a reasonable expectation of success. The skilled artisan would have been motivated to do so since Liu specifically discloses Applicant’s claimed effect on skeletal muscle broadly, which includes the specific skeletal muscles of Applicant’s claim 17, and further in view of the disclosure of Fujiwara, which also discloses that oleuropein effects on specific muscles, such the gastrocnemius, have also been established. The skilled artisan would have been motivated to do so since Horcajada and Liu both teach similar compositions used for the same purpose of generally improving muscle fatigue and weakness and improving musculoskeletal health, and Liu very specifically teaches that this includes exercise, to include strenuous exercise. The skilled artisan would have been motivated to practice the claimed invention with either oleuropein or a metabolite thereof, since Liu teaches improving resistance to muscle fatigue from exercise maintaining or increasing muscle differentiation or regeneration after strenuous physical exercise or under conditions where muscle is chronically inflamed, comprising administering an effective amount of either hydroxytyrosol (HT), or oleuropein used instead of it, or in addition to it, to a mammal, and observing a muscle differentiation effect. (claim 1). Horcajada provides similar motivation to do so since it also teaches increasing and improving muscle functionality (e.g. muscle strength, gait speed, etc.), reducing a loss of muscle functionality (e.g. muscle strength, gait speed, etc.), and improving recovery of muscle functionality after muscle atrophy or injury, in an individual in need thereof, by administering a composition with a therapeutically effective amount of oleuropein. (claim 10, [0057], [0090]). Further motivation to do so is since Horcajada and Liu both teach being able to co-formulated the ingredients as food compositions, dietary supplements, nutritional compositions, etc., and further teaches that they can be reconstituted in water or milk- a further well-known ingredient for promoting bone and muscle health.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3-5, 17 and 19-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10,751,357, and further in view of Hunter, n-3 fatty acids from vegetable oils, Am J Clin Nutr, 1990 May;51(5):809-14 “Hunter”, Abstract, of record), and US 20120302645 A1 to Liu et al. (“Liu”, of record). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons.
The claims of the instant application, are directed to: a method for improving resistance to muscle fatigue from exercise in an individual in need thereof, the method comprising orally administering to the individual an effective amount of at least one of oleuropein, hydroxytyrosol, homovanillyl alcohol, isohomovanillyl alcohol and mixtures thereof in at least one dose during at least one time period selected from the group consisting of (i) a pre-exercise time between one hour and one second prior to initiation of the exercise, (ii) an exercise time between the initiation of the exercise to conclusion of the exercise, and (iii) a post-exercise time between one second and one hour after the conclusion of the exercise, wherein the composition does not comprise hydroxytyrosol, and the exercise is one or more of 1) resistance exercise, 2) anaerobic or repeated sprint-type exercise, or 3) endurance exercise (claim 1), wherein the effective amount of at least one of oleuropein or metabolite thereof is administered in a composition selected from the group consisting of food compositions, dietary supplements, nutritional compositions, nutraceuticals, beverages, powdered nutritional products to be reconstituted in water or milk before consumption, food additives, medicaments, drinks, petfood, and combinations thereof (claim 3), wherein the effective amount of at least one of oleuropein or metabolite thereof is administered in a composition further comprising calcium (claim 4), wherein the effective amount of at least one of oleuropein or metabolite thereof is administered in a food product further comprising a component selected from the group consisting of protein, carbohydrate, fat and mixtures thereof (claim 5).
The claims of the issued patent are directed to: a method of reducing a loss of muscle functionality in an individual, increasing muscle functionality in an individual, and/or improving recovery of muscle functionality after muscle atrophy in an individual, the method consisting of administering a composition comprising an effective amount of oleuropein and an n-3 fatty acid to the individual for a time period of at least 30 consecutive days (claim 1).
Applicant’s claim terms, as presented, are inclusive of a method of reducing a loss of muscle functionality in an individual, increasing muscle functionality in an individual, and/or improving recovery of muscle functionality after muscle atrophy in an individual. Applicant’s claim term “comprising” is open-ended, and does not preclude the addition of other ingredients. Moreover, claim 5 explicitly recites the further addition of fat, and per Applicant’s specification, paragraph [0099], “[n]on-limiting examples of suitable fats include canola oil, corn oil and high-oleic acid sunflower oil.” As further noted by Hunter “principal food sources of the n-3 fatty acid alpha-linolenic acid are salad and cooking oil, salad dressing, shortening, margarine, and food-service fat and oil products made from canola oil or soybean oil.” It is further apparent that the instant Moreover, the claim term “administering” of Applicant’s claim 1 includes administration for at least 30 days, since Applicant’s specification specifically provides so [0085]- “During the time period, the at least one of oleuropein or metabolite thereof and the optional calcium can be administered to the individual at least one day per week; preferably at least two days per week, more preferably at least three, four, five or six days per week; most preferably seven days per week.”
The issued patent does not explicitly use the word “exercise”.
Liu is directed to a method of maintaining or increasing muscle differentiation or regeneration after strenuous physical exercise or under conditions where muscle is chronically inflamed, comprising administering an effective amount of hydroxytyrosol (HT) to a mammal, and observing a muscle differentiation effect. (claim 1).
Liu specifically discloses that: “[0016] In further embodiments of the present invention, hydroxytyrosol derivatives such as esters and physiologically/pharmaceutically acceptable salts may be used instead of or in addition to hydroxytyrosol. It is also possible to use a mixture of hydroxytyrosol and hydroxytyrosol derivatives. Derivatives can be e.g. esters or glucosides, and are known to the person skilled in the art. Preferred esters of hydroxytyrosol are e.g. acetates or glucuronide conjugates; as well as oleuropein being the most preferred one.” (emphasis added).
Thus, even though Applicant has amended claim 1 to recite “wherein the composition does not comprise hydroxytyrosol”, and has argued that removing hydroxytyrosol from the claim would change the principle of operation of Liu, this is clearly not the case. Support for this position is found in paragraph [0016] in the paragraph in the sections with bold and underlining. Thus, the language of the amendment clearly does not remove the disclosure on hydroxytyrosol as relevant. Stated simply, Liu makes explicit that the principle of operation of hydroxytyrosol and oleuropein is interchangeable, and that one may be used instead of the other.
Per Liu, “[0024] When used, hydroxytyrosol has the following benefits: [0025] helps improve effectiveness of your training regimen [0026] helps prevent symptoms of overtraining, [0027] helps reduce delayed onset muscle soreness (DOMS), [0028] helps improve your training outcome after strenuous exercise, [0029] helps your body adapt to exercise better, [0030] helps you to be able to train harder, [0031] helps you reduce the risk to overtrain, [0032] helps improve muscle regeneration after exercise especially strenuous exercise, [0033] helps improve muscle growth after exercise, especially strenuous exercise, [0034] helps muscle regeneration in aching muscles, [0035] supports muscle growth after strenuous exercise, [0036] supports muscle maintenance in elderly, [0037] supports muscle maintenance in Duchenne muscle dystrophy, [0038] supports muscle maintenance in inflammatory muscle wasting conditions.” Per Applicant’s claim 2, the above relate at least to skeletal muscle. Per Applicant’s claim 6, the exercise includes resistance exercise, etc. ([0005]).
The Examiner further notes at least the following relevant sections of Liu: “The pharmaceutical and nutraceutical compositions comprising hydroxytyrosol useful for conditions characterized by altered muscle differentiation especially under inflammatory conditions, such as delayed onset muscle soreness subsequent to strenuous exercise or sarcopenia are provided.” (Abstract). “[0001] This invention is related to the use of hydroxytyrosol ("HT"), or an olive juice extract containing hydroxytyrosol as an agent to improve muscle differentiation and thus improve or maintain the body's adaptation to exercise. It also relates to pharmaceutical and nutraceutical compositions useful for conditions characterized by altered muscle differentiation especially under inflammatory conditions, such as delayed onset muscle soreness subsequent to strenuous exercise or sarcopenia.”
[0004] Muscle differentiation is required for maintenance of the skeletal musculature, for wound healing after surgery, trauma or strenuous exercise. Moreover, the formation of new muscle fibers (myotubes) is required for muscle growth.
[0005] Improving or maintaining muscle differentiation is needed e.g. for adaptation to exercise, especially to resistance exercise, and thus is important for sports performance. Muscle differentiation is also needed for mobility and all associated aspects of health, ability to work, and to lead an active life style.
[0006] Improved muscle differentiation is a particular need of elite athletes, whose professional success depends on an optimized training regimen to be able to perform at top level at times of important competitions. Moreover, healthy muscle differentiation is of interest for life style athletes (recreationally active people, weekend warriors), who harness important experiences of fun and satisfaction from successful exercise performance. Women, who in general have a lower muscle mass than men, often are concerned about their physical capabilities, hence are in need of good muscle differentiation.
[0007] A successful training regimen strives to optimize adaptation of the body to exercise. Adaptation to exercise among others includes an increase in aerobic exercise capacity, increased lipid storage especially in oxidative muscle fibers, activation of the endogenous antioxidant defense system, increased vascularization of the musculature, increased erythropoiesis, synthesis of contractile fibers within muscle cells such as actin and myosin and others, and the recruitment of satellite cells to differentiate and fuse into myotubes.
[0008] Oxidative stress induced by exercise is thought to be causally involved in inducing adaptation to exercise, i.e. successful training. The reactive oxygen species are generated during muscle contractions, but also during aerobic energy metabolism (oxidative phosphorylation, oxphos, aerobic respiration). The redox-sensitive MAPK and NFkB signaling pathways and the resulting reactions of cellular stress and inflammation are regarded as important pathways mediating adaptation to exercise (reviewed in Li Li Ji, Free Radical Biology & Medicine 44 (2008), 142-152, Li Li Ji Exp Gerontology 42 (2007), 582-593). In line with this, intervention studies with the antioxidants allopurinol and vitamin C in animal models and in humans have found that antioxidant supplementation reduced adaptation to exercise (Gomez-Carbrera et al. 2005 J Physiol 567, 113-120, Gomez-Carbrera et al. 2008 Am. J. Clin. Nutr. 87(1):142-149, Ristow et al (2009) PNAS 106, 8665-8670).
([0004]- [0008]; emphasis added).
As an additional example showing teaching improving of muscle fatigue or weakness from exercise in Liu, the Examiner notes the endurance exercise procedure experiment in rats.
Endurance Exercise Procedure
[0085] Rats were randomly divided into four groups: Sedentary, Sedentary with HT supplement (25 mg/kg/day), Endurance exercise and Endurance exercise with HT supplement (25 mg/kg/day). HT was administrated by gavage 45 min before exercise program for each animal. Rats were run on a motorized treadmill at a speed of 20 m/min and a grade of 5.degree. for 1 hour per day and 6 days per week. After 8 weeks exercise, endurance capacity was measured by treadmill running to exhaustion at a speed of 30 m/min and a grade of 5.degree.. Exhaustion was defined as the inability to maintain running and avoid sound and light irritation.
Isolation of Skeletal Muscle Mitochondria
[0086] The soleus muscle was removed from each leg. A first portion was frozen in liquid N.sub.2 and used for total RNA and protein extraction. A second portion was used immediately for mitochondrial isolation. Soleus muscles were trimmed off fat and connective tissue, chopped finely with a pair of scissors, and used for mitochondrial isolation.
[. . .]
LTE (Long Term Exercise) on Endurance Capacity and Muscle Atrophy and the Effect of HT Supplement
[0092] We performed a LTE program with rats and studied the effects of HT supplement on physical performance and the underlying mechanism of mitochondrial dynamics. We showed that LTE was prone to reduce endurance capacity, and HT supplement was sufficient to improve endurance capacity of exercise rats by 35% without any effect on sedentary rats (FIG. 9A).”
Accordingly, it would have been obvious to a person of skill in the art before the effective filing date of the claimed invention to optimize the time period of exercise, its intensity and duration relative to the administration of oleuropein or a metabolite thereof, as per Applicant’s claims, based on the disclosure of Liu. The skilled artisan would have been motivated to do so since Liu specifically discloses optimizing the exercise regimen taking into account various specifically enumerated considerations, and further in view of the need to intake a dietary supplement comprising oleuropein or a metabolite thereof so as to further optimize the process of muscle differentiation.
Timing of administration impacts drug pharmacokinetics, and is therefore a result- effective variable, which is subject to optimization. See MPEP 2144.05.
B.There is a Motivation to Optimize Result-Effective Variables
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process.
Therefore, a prima facie case of obviousness has been properly made. Applicant has failed to rebut it, with either argument, or data. For instance, there is nothing of record to show any criticality of Applicant’s claimed timing of administration. There is a sole paragraph in Applicant’s specification, devoid of any further data whatsoever, which simply just generally states that administering close to the time of exercise is selected.
“[0006] In an embodiment, the at least one of oleuropein or metabolite thereof is administered in at least one dose during at least one time period selected from the group consisting of (i) a pre-exercise time between one hour prior to initiation of the exercise and one second prior to the initiation of the exercise, such as between thirty minutes prior to the initiation of the exercise and one minute prior to the initiation of the exercise, (ii) an exercise time between the initiation of the exercise to conclusion of the exercise, and (i) a post-exercise time between one second after the conclusion of the exercise and one hour after the conclusion of the exercise, such as between one minute after the conclusion of the exercise and thirty minutes after the conclusion of the exercise.”
It is noted that administering an energy supplement close to the time when energy is needed is indeed obvious and subject to optimization. Generally, it is not inventive to discover such regimens by routine experimentation when the general conditions of a claim are disclosed in the prior art. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) and MPEP §2144.05(11). The medical arts recognize that drug therapy may be optimized by designing regimens that account for the concentration of a drug, for example, to achieve a desired pharmacological response. The factual underpinnings for doing so are further found in references of record, as well as supported by well-established precedent on optimization.
Accordingly, Liu discloses Applicant’s claimed method. As the Federal Circuit holds, the elements must be arranged as required by the claim, but this is not an ipsissimis verbis test, i.e., identity of terminology is not required. In re Bond, 910 F.2d 831, 15 USPQ2d 1566 (Fed. Cir. 1990). See also MPEP 2131.
Accordingly, it would have been obvious to a person of skill in the art before the effective filing date of the claimed invention to combine the teachings of the issued patent, Hunter and Lu in order to practice Applicant’s claimed method with a composition, which comprises both oleuropein and n-3 fatty acids. The skilled artisan would have been motivated to so since the instant claims clearly recite co-formulating with additional ingredients, such as fat, and in a food product, and the specification further discloses that such suitable fats include, for instance canola oil. As is further made evident by Hunter, canola oil is a principal food source of n-3 fatty acid alpha-linoleic acid. This discloses overlapping subject matter, which is further known obvious by the food nature of the claimed compositions, and the presence of n-3 fatty acids in them. Further motivation to do so is in view of Liu, which explicitly discloses that the improvement of musculoskeletal benefits specifically extend to exercise and training benefits.
Claims 1, 3-5, 17 and 19-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-9 of U.S. Patent No. 11,364,254, and further in view of Hunter, n-3 fatty acids from vegetable oils, Am J Clin Nutr, 1990 May;51(5):809-14 “Hunter”, Abstract, of record), and Food Sources of Vitamin D, Data Source: U.S. Department of Agriculture, Agricultural Research Service. FoodData Central, 2019, fdc.nal.usda.gov, available at https://www.dietaryguidelines.gov/resources/2020-2025-dietary-guidelines-online-materials/food-sources-select-nutrients/food-sources-vitamin-d. (“Food Sources of Vitamin D), and US 20120302645 A1 to Liu et al. (“Liu”, of record). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons.
The claims of the instant application, are directed to: a method for improving resistance to muscle fatigue from exercise in an individual in need thereof, the method comprising orally administering to the individual an effective amount of at least one of oleuropein, hydroxytyrosol, homovanillyl alcohol, isohomovanillyl alcohol and mixtures thereof in at least one dose during at least one time period selected from the group consisting of (i) a pre-exercise time between one hour and one second prior to initiation of the exercise, (ii) an exercise time between the initiation of the exercise to conclusion of the exercise, and (iii) a post-exercise time between one second and one hour after the conclusion of the exercise, wherein the composition does not comprise hydroxytyrosol, and the exercise is one or more of 1) resistance exercise, 2) anaerobic or repeated sprint-type exercise, or 3) endurance exercise (claim 1), wherein the effective amount of at least one of oleuropein or metabolite thereof is administered in a composition selected from the group consisting of food compositions, dietary supplements, nutritional compositions, nutraceuticals, beverages, powdered nutritional products to be reconstituted in water or milk before consumption, food additives, medicaments, drinks, petfood, and combinations thereof (claim 3), wherein the effective amount of at least one of oleuropein or metabolite thereof is administered in a composition further comprising calcium (claim 4), wherein the effective amount of at least one of oleuropein or metabolite thereof is administered in a food product further comprising a component selected from the group consisting of protein, carbohydrate, fat and mixtures thereof (claim 5).
The claims of the issued patent are directed to: a method of reducing a loss of muscle functionality, increasing muscle functionality and/or improving recovery of muscle functionality after muscle atrophy in an individual in need thereof, the method comprising administering to the individual a composition comprising (i) 0.01 mg to about 1.0 g of oleuropein per serving as the only polyphenol, (ii) a fatty acid, (iii) branched chain amino acids comprising leucine, isoleucine and valine, (iv) 800 to 1200 IU of Vitamin D per serving, and (v) whey protein, wherein the composition is administered in a daily amount comprising 5 g to 50 g of the whey protein per day (claim 1), wherein the fatty acid is an n-3 fatty acid (claim 3), wherein the composition further comprises a protein selected from the group consisting of casein, pea protein, soy protein and combinations thereof (claim 4), wherein the individual has sarcopenia (claim 5), wherein the composition is administered to the individual for a time period comprising at least 30 consecutive days (claim 9).
Applicant’s claim terms, as presented, are inclusive of a method of reducing a loss of muscle functionality, increasing muscle functionality and/or improving recovery of muscle functionality after muscle atrophy in an individual in need thereof. Applicant’s claim term “comprising” is open-ended, and does not preclude the addition of other ingredients. Moreover, claim 5 explicitly recites the further addition of protein, carbohydrate and fat. Further, per Applicant’s specification, treatment of sarcopenia is also encompassed by the claimed method of treatment, as Applicant’s specification provides that sarcopenia is defined as the age-associated loss of muscle mass and functionality (including muscle strength and gait speed). ([0002]).
Per Applicant’s specification, paragraph [0099], “[n]on-limiting examples of suitable fats include canola oil, corn oil and high-oleic acid sunflower oil.” As further noted by Hunter “principal food sources of the n-3 fatty acid alpha-linolenic acid are salad and cooking oil, salad dressing, shortening, margarine, and food-service fat and oil products made from canola oil or soybean oil.”
Moreover, amino acids are the building block of proteins, and Applicant’s specification specifically discloses that “the protein source in the composition may comprise leucine in free form and/or leucine bound as peptides and/or proteins such as dairy, animal or vegetable proteins.” ([0096]). Per Applicant’s specification, paragraph [0093], protein encompasses, e.g. “milk proteins, soy proteins, and/or pea proteins. In a preferred embodiment, the protein source is selected from the group consisting of whey protein; casein protein; pea protein; soy protein; wheat protein; corn protein; rice protein; proteins from legumes, cereals and grains; and combinations thereof.”
Further, milk proteins, soy proteins, etc. are a dietary source of vitamin D. See, e.g. Food Sources of Vitamin D.
Moreover, the claim term “administering” of Applicant’s claim 1 includes administration for at least 30 days, since Applicant’s specification specifically provides so [0085]- “During the time period, the at least one of oleuropein or metabolite thereof and the optional calcium can be administered to the individual at least one day per week; preferably at least two days per week, more preferably at least three, four, five or six days per week; most preferably seven days per week.”
The issued patent does not explicitly use the word “exercise”.
Liu is directed to a method of maintaining or increasing muscle differentiation or regeneration after strenuous physical exercise or under conditions where muscle is chronically inflamed, comprising administering an effective amount of hydroxytyrosol (HT) to a mammal, and observing a muscle differentiation effect. (claim 1).
Liu specifically discloses that: “[0016] In further embodiments of the present invention, hydroxytyrosol derivatives such as esters and physiologically/pharmaceutically acceptable salts may be used instead of or in addition to hydroxytyrosol. It is also possible to use a mixture of hydroxytyrosol and hydroxytyrosol derivatives. Derivatives can be e.g. esters or glucosides, and are known to the person skilled in the art. Preferred esters of hydroxytyrosol are e.g. acetates or glucuronide conjugates; as well as oleuropein being the most preferred one.” (emphasis added).
Thus, even though Applicant has amended claim 1 to recite “wherein the composition does not comprise hydroxytyrosol”, and has argued that removing hydroxytyrosol from the claim would change the principle of operation of Liu, this is clearly not the case. Support for this position is found in paragraph [0016] in the paragraph in the sections with bold and underlining. Thus, the language of the amendment clearly does not remove the disclosure on hydroxytyrosol as relevant. Stated simply, Liu makes explicit that the principle of operation of hydroxytyrosol and oleuropein is interchangeable, and that one may be used instead of the other.
Per Liu, “[0024] When used, hydroxytyrosol has the following benefits: [0025] helps improve effectiveness of your training regimen [0026] helps prevent symptoms of overtraining, [0027] helps reduce delayed onset muscle soreness (DOMS), [0028] helps improve your training outcome after strenuous exercise, [0029] helps your body adapt to exercise better, [0030] helps you to be able to train harder, [0031] helps you reduce the risk to overtrain, [0032] helps improve muscle regeneration after exercise especially strenuous exercise, [0033] helps improve muscle growth after exercise, especially strenuous exercise, [0034] helps muscle regeneration in aching muscles, [0035] supports muscle growth after strenuous exercise, [0036] supports muscle maintenance in elderly, [0037] supports muscle maintenance in Duchenne muscle dystrophy, [0038] supports muscle maintenance in inflammatory muscle wasting conditions.” Per Applicant’s claim 2, the above relate at least to skeletal muscle. Per Applicant’s claim 6, the exercise includes resistance exercise, etc. ([0005]).
The Examiner further notes at least the following relevant sections of Liu: “The pharmaceutical and nutraceutical compositions comprising hydroxytyrosol useful for conditions characterized by altered muscle differentiation especially under inflammatory conditions, such as delayed onset muscle soreness subsequent to strenuous exercise or sarcopenia are provided.” (Abstract). “[0001] This invention is related to the use of hydroxytyrosol ("HT"), or an olive juice extract containing hydroxytyrosol as an agent to improve muscle differentiation and thus improve or maintain the body's adaptation to exercise. It also relates to pharmaceutical and nutraceutical compositions useful for conditions characterized by altered muscle differentiation especially under inflammatory conditions, such as delayed onset muscle soreness subsequent to strenuous exercise or sarcopenia.”
[0004] Muscle differentiation is required for maintenance of the skeletal musculature, for wound healing after surgery, trauma or strenuous exercise. Moreover, the formation of new muscle fibers (myotubes) is required for muscle growth.
[0005] Improving or maintaining muscle differentiation is needed e.g. for adaptation to exercise, especially to resistance exercise, and thus is important for sports performance. Muscle differentiation is also needed for mobility and all associated aspects of health, ability to work, and to lead an active life style.
[0006] Improved muscle differentiation is a particular need of elite athletes, whose professional success depends on an optimized training regimen to be able to perform at top level at times of important competitions. Moreover, healthy muscle differentiation is of interest for life style athletes (recreationally active people, weekend warriors), who harness important experiences of fun and satisfaction from successful exercise performance. Women, who in general have a lower muscle mass than men, often are concerned about their physical capabilities, hence are in need of good muscle differentiation.
[0007] A successful training regimen strives to optimize adaptation of the body to exercise. Adaptation to exercise among others includes an increase in aerobic exercise capacity, increased lipid storage especially in oxidative muscle fibers, activation of the endogenous antioxidant defense system, increased vascularization of the musculature, increased erythropoiesis, synthesis of contractile fibers within muscle cells such as actin and myosin and others, and the recruitment of satellite cells to differentiate and fuse into myotubes.
[0008] Oxidative stress induced by exercise is thought to be causally involved in inducing adaptation to exercise, i.e. successful training. The reactive oxygen species are generated during muscle contractions, but also during aerobic energy metabolism (oxidative phosphorylation, oxphos, aerobic respiration). The redox-sensitive MAPK and NFkB signaling pathways and the resulting reactions of cellular stress and inflammation are regarded as important pathways mediating adaptation to exercise (reviewed in Li Li Ji, Free Radical Biology & Medicine 44 (2008), 142-152, Li Li Ji Exp Gerontology 42 (2007), 582-593). In line with this, intervention studies with the antioxidants allopurinol and vitamin C in animal models and in humans have found that antioxidant supplementation reduced adaptation to exercise (Gomez-Carbrera et al. 2005 J Physiol 567, 113-120, Gomez-Carbrera et al. 2008 Am. J. Clin. Nutr. 87(1):142-149, Ristow et al (2009) PNAS 106, 8665-8670).
([0004]- [0008]; emphasis added).
As an additional example showing teaching improving of muscle fatigue or weakness from exercise in Liu, the Examiner notes the endurance exercise procedure experiment in rats.
Endurance Exercise Procedure
[0085] Rats were randomly divided into four groups: Sedentary, Sedentary with HT supplement (25 mg/kg/day), Endurance exercise and Endurance exercise with HT supplement (25 mg/kg/day). HT was administrated by gavage 45 min before exercise program for each animal. Rats were run on a motorized treadmill at a speed of 20 m/min and a grade of 5.degree. for 1 hour per day and 6 days per week. After 8 weeks exercise, endurance capacity was measured by treadmill running to exhaustion at a speed of 30 m/min and a grade of 5.degree.. Exhaustion was defined as the inability to maintain running and avoid sound and light irritation.
Isolation of Skeletal Muscle Mitochondria
[0086] The soleus muscle was removed from each leg. A first portion was frozen in liquid N.sub.2 and used for total RNA and protein extraction. A second portion was used immediately for mitochondrial isolation. Soleus muscles were trimmed off fat and connective tissue, chopped finely with a pair of scissors, and used for mitochondrial isolation.
[. . .]
LTE (Long Term Exercise) on Endurance Capacity and Muscle Atrophy and the Effect of HT Supplement
[0092] We performed a LTE program with rats and studied the effects of HT supplement on physical performance and the underlying mechanism of mitochondrial dynamics. We showed that LTE was prone to reduce endurance capacity, and HT supplement was sufficient to improve endurance capacity of exercise rats by 35% without any effect on sedentary rats (FIG. 9A).”
Accordingly, it would have been obvious to a person of skill in the art before the effective filing date of the claimed invention to optimize the time period of exercise, its intensity and duration relative to the administration of oleuropein or a metabolite thereof, as per Applicant’s claims, based on the disclosure of Liu. The skilled artisan would have been motivated to do so since Liu specifically discloses optimizing the exercise regimen taking into account various specifically enumerated considerations, and further in view of the need to intake a dietary supplement comprising oleuropein or a metabolite thereof so as to further optimize the process of muscle differentiation.
Timing of administration impacts drug pharmacokinetics, and is therefore a result- effective variable, which is subject to optimization. See MPEP 2144.05.
B.There is a Motivation to Optimize Result-Effective Variables
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process.
Therefore, a prima facie case of obviousness has been properly made. Applicant has failed to rebut it, with either argument, or data. For instance, there is nothing of record to show any criticality of Applicant’s claimed timing of administration. There is a sole paragraph in Applicant’s specification, devoid of any further data whatsoever, which simply just generally states that administering close to the time of exercise is selected.
“[0006] In an embodiment, the at least one of oleuropein or metabolite thereof is administered in at least one dose during at least one time period selected from the group consisting of (i) a pre-exercise time between one hour prior to initiation of the exercise and one second prior to the initiation of the exercise, such as between thirty minutes prior to the initiation of the exercise and one minute prior to the initiation of the exercise, (ii) an exercise time between the initiation of the exercise to conclusion of the exercise, and (i) a post-exercise time between one second after the conclusion of the exercise and one hour after the conclusion of the exercise, such as between one minute after the conclusion of the exercise and thirty minutes after the conclusion of the exercise.”
It is noted that administering an energy supplement close to the time when energy is needed is indeed obvious and subject to optimization. Generally, it is not inventive to discover such regimens by routine experimentation when the general conditions of a claim are disclosed in the prior art. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) and MPEP §2144.05(11). The medical arts recognize that drug therapy may be optimized by designing regimens that account for the concentration of a drug, for example, to achieve a desired pharmacological response. The factual underpinnings for doing so are further found in references of record, as well as supported by well-established precedent on optimization.
Accordingly, Liu discloses Applicant’s claimed method. As the Federal Circuit holds, the elements must be arranged as required by the claim, but this is not an ipsissimis verbis test, i.e., identity of terminology is not required. In re Bond, 910 F.2d 831, 15 USPQ2d 1566 (Fed. Cir. 1990). See also MPEP 2131.
Accordingly, it would have been obvious to a person of skill in the art before the effective filing date of the claimed invention to combine the teachings of the issued patent, Hunter, Food Sources of Vitamin D and Liu, in order to practice Applicant’s claimed method with a composition, which comprises both oleuropein and n-3 fatty acids. The skilled artisan would have been motivated to so since the instant claims clearly recite co-formulating with additional ingredients, such as fat and protein, and in a food product. The specification further discloses that such suitable fats include, for instance canola oil. As is further made evident by Hunter, canola oil is a principal food source of n-3 fatty acid alpha-linoleic acid. The specification further discloses that the term “protein” specifically encompasses claimed proteins in the issued patent. Moreover, claimed protein sources, e.g. milk and soy, further include vitamin D, as disclosed in Food Sources of Vitamin D, and Applicant’s claim 6 even further discloses reconstituting the composition in milk. This discloses overlapping subject matter, which is further known obvious by the food nature of the claimed compositions, and the presence of the additional claimed ingredients in them. Further motivation to do so is in view of Liu, which explicitly discloses that the improvement of musculoskeletal benefits specifically extend to exercise and training benefits.
Claims 1, 3-5, 17 and 19-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 11,813,273, and further in view of Hunter, n-3 fatty acids from vegetable oils, Am J Clin Nutr, 1990 May;51(5):809-14 “Hunter”, Abstract, of record), and US 20120302645 A1 to Liu et al. (“Liu”, of record). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons.
The claims of the instant application, are directed to: a method for improving resistance to muscle fatigue from exercise in an individual in need thereof, the method comprising orally administering to the individual an effective amount of at least one of oleuropein, hydroxytyrosol, homovanillyl alcohol, isohomovanillyl alcohol and mixtures thereof in at least one dose during at least one time period selected from the group consisting of (i) a pre-exercise time between one hour and one second prior to initiation of the exercise, (ii) an exercise time between the initiation of the exercise to conclusion of the exercise, and (iii) a post-exercise time between one second and one hour after the conclusion of the exercise, wherein the composition does not comprise hydroxytyrosol, and the exercise is one or more of 1) resistance exercise, 2) anaerobic or repeated sprint-type exercise, or 3) endurance exercise (claim 1), wherein the effective amount of at least one of oleuropein or metabolite thereof is administered in a composition selected from the group consisting of food compositions, dietary supplements, nutritional compositions, nutraceuticals, beverages, powdered nutritional products to be reconstituted in water or milk before consumption, food additives, medicaments, drinks, petfood, and combinations thereof (claim 3), wherein the effective amount of at least one of oleuropein or metabolite thereof is administered in a composition further comprising calcium (claim 4), wherein the effective amount of at least one of oleuropein or metabolite thereof is administered in a food product further comprising a component selected from the group consisting of protein, carbohydrate, fat and mixtures thereof (claim 5).
The claims of the issued patent are directed to: a method of reducing a loss of muscle functionality in an individual, increasing muscle functionality in an individual, and/or improving recovery of muscle functionality after muscle atrophy in an individual, the method comprising administering a composition comprising a polyphenol and whey protein to the individual (claim 1), wherein the polyphenol is selected from the group consisting of oleuropein, rutin, quercetin, curcumin and combinations thereof (claim 2), wherein the composition comprises a fatty acid (claim 3), wherein the fatty acid is an n-3 fatty acid, wherein the composition further comprises another protein selected from the group consisting of casein, pea protein, soy protein and combinations thereof (claim 5), wherein the composition further comprises a protein selected from the group consisting of casein, pea protein, soy protein and combinations thereof (claim 4), wherein the individual has sarcopenia (claim 5), wherein the composition further comprises a plant protein selected from the group consisting of pea protein, soy protein and combinations thereof (claim 12).
Applicant’s claim terms, as presented, are inclusive of a method of reducing a loss of muscle functionality in an individual, increasing muscle functionality in an individual, and/or improving recovery of muscle functionality after muscle atrophy in an individual. Applicant’s claim term “comprising” is open-ended, and does not preclude the addition of other ingredients. Moreover, claim 5 explicitly recites the further addition of protein, carbohydrate and fat
Per Applicant’s specification, paragraph [0099], “[n]on-limiting examples of suitable fats include canola oil, corn oil and high-oleic acid sunflower oil.” As further noted by Hunter “principal food sources of the n-3 fatty acid alpha-linolenic acid are salad and cooking oil, salad dressing, shortening, margarine, and food-service fat and oil products made from canola oil or soybean oil.”
Moreover, Applicant’s specification specifically discloses that “the protein source in the composition may comprise leucine in free form and/or leucine bound as peptides and/or proteins such as dairy, animal or vegetable proteins.” ([0096]). Per Applicant’s specification, paragraph [0093], protein encompasses, e.g. “milk proteins, soy proteins, and/or pea proteins. In a preferred embodiment, the protein source is selected from the group consisting of whey protein; casein protein; pea protein; soy protein; wheat protein; corn protein; rice protein; proteins from legumes, cereals and grains; and combinations thereof.”
The issued patent does not explicitly use the word “exercise”.
Liu is directed to a method of maintaining or increasing muscle differentiation or regeneration after strenuous physical exercise or under conditions where muscle is chronically inflamed, comprising administering an effective amount of hydroxytyrosol (HT) to a mammal, and observing a muscle differentiation effect. (claim 1).
Liu specifically discloses that: “[0016] In further embodiments of the present invention, hydroxytyrosol derivatives such as esters and physiologically/pharmaceutically acceptable salts may be used instead of or in addition to hydroxytyrosol. It is also possible to use a mixture of hydroxytyrosol and hydroxytyrosol derivatives. Derivatives can be e.g. esters or glucosides, and are known to the person skilled in the art. Preferred esters of hydroxytyrosol are e.g. acetates or glucuronide conjugates; as well as oleuropein being the most preferred one.” (emphasis added).
Thus, even though Applicant has amended claim 1 to recite “wherein the composition does not comprise hydroxytyrosol”, and has argued that removing hydroxytyrosol from the claim would change the principle of operation of Liu, this is clearly not the case. Support for this position is found in paragraph [0016] in the paragraph in the sections with bold and underlining. Thus, the language of the amendment clearly does not remove the disclosure on hydroxytyrosol as relevant. Stated simply, Liu makes explicit that the principle of operation of hydroxytyrosol and oleuropein is interchangeable, and that one may be used instead of the other.
Per Liu, “[0024] When used, hydroxytyrosol has the following benefits: [0025] helps improve effectiveness of your training regimen [0026] helps prevent symptoms of overtraining, [0027] helps reduce delayed onset muscle soreness (DOMS), [0028] helps improve your training outcome after strenuous exercise, [0029] helps your body adapt to exercise better, [0030] helps you to be able to train harder, [0031] helps you reduce the risk to overtrain, [0032] helps improve muscle regeneration after exercise especially strenuous exercise, [0033] helps improve muscle growth after exercise, especially strenuous exercise, [0034] helps muscle regeneration in aching muscles, [0035] supports muscle growth after strenuous exercise, [0036] supports muscle maintenance in elderly, [0037] supports muscle maintenance in Duchenne muscle dystrophy, [0038] supports muscle maintenance in inflammatory muscle wasting conditions.” Per Applicant’s claim 2, the above relate at least to skeletal muscle. Per Applicant’s claim 6, the exercise includes resistance exercise, etc. ([0005]).
The Examiner further notes at least the following relevant sections of Liu: “The pharmaceutical and nutraceutical compositions comprising hydroxytyrosol useful for conditions characterized by altered muscle differentiation especially under inflammatory conditions, such as delayed onset muscle soreness subsequent to strenuous exercise or sarcopenia are provided.” (Abstract). “[0001] This invention is related to the use of hydroxytyrosol ("HT"), or an olive juice extract containing hydroxytyrosol as an agent to improve muscle differentiation and thus improve or maintain the body's adaptation to exercise. It also relates to pharmaceutical and nutraceutical compositions useful for conditions characterized by altered muscle differentiation especially under inflammatory conditions, such as delayed onset muscle soreness subsequent to strenuous exercise or sarcopenia.”
[0004] Muscle differentiation is required for maintenance of the skeletal musculature, for wound healing after surgery, trauma or strenuous exercise. Moreover, the formation of new muscle fibers (myotubes) is required for muscle growth.
[0005] Improving or maintaining muscle differentiation is needed e.g. for adaptation to exercise, especially to resistance exercise, and thus is important for sports performance. Muscle differentiation is also needed for mobility and all associated aspects of health, ability to work, and to lead an active life style.
[0006] Improved muscle differentiation is a particular need of elite athletes, whose professional success depends on an optimized training regimen to be able to perform at top level at times of important competitions. Moreover, healthy muscle differentiation is of interest for life style athletes (recreationally active people, weekend warriors), who harness important experiences of fun and satisfaction from successful exercise performance. Women, who in general have a lower muscle mass than men, often are concerned about their physical capabilities, hence are in need of good muscle differentiation.
[0007] A successful training regimen strives to optimize adaptation of the body to exercise. Adaptation to exercise among others includes an increase in aerobic exercise capacity, increased lipid storage especially in oxidative muscle fibers, activation of the endogenous antioxidant defense system, increased vascularization of the musculature, increased erythropoiesis, synthesis of contractile fibers within muscle cells such as actin and myosin and others, and the recruitment of satellite cells to differentiate and fuse into myotubes.
[0008] Oxidative stress induced by exercise is thought to be causally involved in inducing adaptation to exercise, i.e. successful training. The reactive oxygen species are generated during muscle contractions, but also during aerobic energy metabolism (oxidative phosphorylation, oxphos, aerobic respiration). The redox-sensitive MAPK and NFkB signaling pathways and the resulting reactions of cellular stress and inflammation are regarded as important pathways mediating adaptation to exercise (reviewed in Li Li Ji, Free Radical Biology & Medicine 44 (2008), 142-152, Li Li Ji Exp Gerontology 42 (2007), 582-593). In line with this, intervention studies with the antioxidants allopurinol and vitamin C in animal models and in humans have found that antioxidant supplementation reduced adaptation to exercise (Gomez-Carbrera et al. 2005 J Physiol 567, 113-120, Gomez-Carbrera et al. 2008 Am. J. Clin. Nutr. 87(1):142-149, Ristow et al (2009) PNAS 106, 8665-8670).
([0004]- [0008]; emphasis added).
As an additional example showing teaching improving of muscle fatigue or weakness from exercise in Liu, the Examiner notes the endurance exercise procedure experiment in rats.
Endurance Exercise Procedure
[0085] Rats were randomly divided into four groups: Sedentary, Sedentary with HT supplement (25 mg/kg/day), Endurance exercise and Endurance exercise with HT supplement (25 mg/kg/day). HT was administrated by gavage 45 min before exercise program for each animal. Rats were run on a motorized treadmill at a speed of 20 m/min and a grade of 5.degree. for 1 hour per day and 6 days per week. After 8 weeks exercise, endurance capacity was measured by treadmill running to exhaustion at a speed of 30 m/min and a grade of 5.degree.. Exhaustion was defined as the inability to maintain running and avoid sound and light irritation.
Isolation of Skeletal Muscle Mitochondria
[0086] The soleus muscle was removed from each leg. A first portion was frozen in liquid N.sub.2 and used for total RNA and protein extraction. A second portion was used immediately for mitochondrial isolation. Soleus muscles were trimmed off fat and connective tissue, chopped finely with a pair of scissors, and used for mitochondrial isolation.
[. . .]
LTE (Long Term Exercise) on Endurance Capacity and Muscle Atrophy and the Effect of HT Supplement
[0092] We performed a LTE program with rats and studied the effects of HT supplement on physical performance and the underlying mechanism of mitochondrial dynamics. We showed that LTE was prone to reduce endurance capacity, and HT supplement was sufficient to improve endurance capacity of exercise rats by 35% without any effect on sedentary rats (FIG. 9A).”
Accordingly, it would have been obvious to a person of skill in the art before the effective filing date of the claimed invention to optimize the time period of exercise, its intensity and duration relative to the administration of oleuropein or a metabolite thereof, as per Applicant’s claims, based on the disclosure of Liu. The skilled artisan would have been motivated to do so since Liu specifically discloses optimizing the exercise regimen taking into account various specifically enumerated considerations, and further in view of the need to intake a dietary supplement comprising oleuropein or a metabolite thereof so as to further optimize the process of muscle differentiation.
Timing of administration impacts drug pharmacokinetics, and is therefore a result- effective variable, which is subject to optimization. See MPEP 2144.05.
B.There is a Motivation to Optimize Result-Effective Variables
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process.
Therefore, a prima facie case of obviousness has been properly made. Applicant has failed to rebut it, with either argument, or data. For instance, there is nothing of record to show any criticality of Applicant’s claimed timing of administration. There is a sole paragraph in Applicant’s specification, devoid of any further data whatsoever, which simply just generally states that administering close to the time of exercise is selected.
“[0006] In an embodiment, the at least one of oleuropein or metabolite thereof is administered in at least one dose during at least one time period selected from the group consisting of (i) a pre-exercise time between one hour prior to initiation of the exercise and one second prior to the initiation of the exercise, such as between thirty minutes prior to the initiation of the exercise and one minute prior to the initiation of the exercise, (ii) an exercise time between the initiation of the exercise to conclusion of the exercise, and (i) a post-exercise time between one second after the conclusion of the exercise and one hour after the conclusion of the exercise, such as between one minute after the conclusion of the exercise and thirty minutes after the conclusion of the exercise.”
It is noted that administering an energy supplement close to the time when energy is needed is indeed obvious and subject to optimization. Generally, it is not inventive to discover such regimens by routine experimentation when the general conditions of a claim are disclosed in the prior art. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) and MPEP §2144.05(11). The medical arts recognize that drug therapy may be optimized by designing regimens that account for the concentration of a drug, for example, to achieve a desired pharmacological response. The factual underpinnings for doing so are further found in references of record, as well as supported by well-established precedent on optimization.
Accordingly, Liu discloses Applicant’s claimed method. As the Federal Circuit holds, the elements must be arranged as required by the claim, but this is not an ipsissimis verbis test, i.e., identity of terminology is not required. In re Bond, 910 F.2d 831, 15 USPQ2d 1566 (Fed. Cir. 1990). See also MPEP 2131.
Accordingly, it would have been obvious to a person of skill in the art before the effective filing date of the claimed invention to combine the teachings of the issued patent, Hunter and Liu, in order to practice Applicant’s claimed method with a composition, which comprises both oleuropein and n-3 fatty acids. The skilled artisan would have been motivated to so since the instant claims clearly recite co-formulating with additional ingredients, such as fat and protein, and in a food product. The specification further discloses that such suitable fats include, for instance canola oil. As is further made evident by Hunter, canola oil is a principal food source of n-3 fatty acid alpha-linoleic acid. The specification further discloses that the term “protein” specifically encompasses claimed proteins in the issued patent. This discloses overlapping subject matter, which is further known obvious by the food nature of the claimed compositions, and the presence of the additional claimed ingredients in them. Further motivation to do so is in view of Liu, which explicitly discloses that the improvement of musculoskeletal benefits specifically extend to exercise and training benefits.
Claims 1, 3-5, 17 and 19-24 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 18 and 19 of copending Application No. 17/595,159 (reference application), and US 20120302645 A1 to Liu et al. (“Liu”, of record). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reasons.
The claims of the instant application, are directed to: a method for improving resistance to muscle fatigue from exercise in an individual in need thereof, the method comprising orally administering to the individual an effective amount of at least one of oleuropein, hydroxytyrosol, homovanillyl alcohol, isohomovanillyl alcohol and mixtures thereof in at least one dose during at least one time period selected from the group consisting of (i) a pre-exercise time between one hour and one second prior to initiation of the exercise, (ii) an exercise time between the initiation of the exercise to conclusion of the exercise, and (iii) a post-exercise time between one second and one hour after the conclusion of the exercise, wherein the composition does not comprise hydroxytyrosol, and the exercise is one or more of 1) resistance exercise, 2) anaerobic or repeated sprint-type exercise, or 3) endurance exercise (claim 1), wherein the effective amount of at least one of oleuropein or metabolite thereof is administered in a composition selected from the group consisting of food compositions, dietary supplements, nutritional compositions, nutraceuticals, beverages, powdered nutritional products to be reconstituted in water or milk before consumption, food additives, medicaments, drinks, petfood, and combinations thereof (claim 3), wherein the effective amount of at least one of oleuropein or metabolite thereof is administered in a composition further comprising calcium (claim 4), wherein the effective amount of at least one of oleuropein or metabolite thereof is administered in a food product further comprising a component selected from the group consisting of protein, carbohydrate, fat and mixtures thereof (claim 5).
The claims of the co-pending application are directed to: a method of achieving at least one result selected from the group consisting of . . . (iv) improvement in at least one of muscle functionality, muscle performance, or muscle strength, (v) decreased muscle fatigue, (vi) increased mobility and (vii) treatment of a muscle disorder linked to calcium depletion or deficiency, the method comprising orally administering to an individual an effective amount of a combination of calcium and oleuropein (claim 1).
The co-pending patent application does not explicitly use the word “exercise”.
Liu is directed to a method of maintaining or increasing muscle differentiation or regeneration after strenuous physical exercise or under conditions where muscle is chronically inflamed, comprising administering an effective amount of hydroxytyrosol (HT) to a mammal, and observing a muscle differentiation effect. (claim 1).
Liu specifically discloses that: “[0016] In further embodiments of the present invention, hydroxytyrosol derivatives such as esters and physiologically/pharmaceutically acceptable salts may be used instead of or in addition to hydroxytyrosol. It is also possible to use a mixture of hydroxytyrosol and hydroxytyrosol derivatives. Derivatives can be e.g. esters or glucosides, and are known to the person skilled in the art. Preferred esters of hydroxytyrosol are e.g. acetates or glucuronide conjugates; as well as oleuropein being the most preferred one.” (emphasis added).
Thus, even though Applicant has amended claim 1 to recite “wherein the composition does not comprise hydroxytyrosol”, and has argued that removing hydroxytyrosol from the claim would change the principle of operation of Liu, this is clearly not the case. Support for this position is found in paragraph [0016] in the paragraph in the sections with bold and underlining. Thus, the language of the amendment clearly does not remove the disclosure on hydroxytyrosol as relevant. Stated simply, Liu makes explicit that the principle of operation of hydroxytyrosol and oleuropein is interchangeable, and that one may be used instead of the other.
Per Liu, “[0024] When used, hydroxytyrosol has the following benefits: [0025] helps improve effectiveness of your training regimen [0026] helps prevent symptoms of overtraining, [0027] helps reduce delayed onset muscle soreness (DOMS), [0028] helps improve your training outcome after strenuous exercise, [0029] helps your body adapt to exercise better, [0030] helps you to be able to train harder, [0031] helps you reduce the risk to overtrain, [0032] helps improve muscle regeneration after exercise especially strenuous exercise, [0033] helps improve muscle growth after exercise, especially strenuous exercise, [0034] helps muscle regeneration in aching muscles, [0035] supports muscle growth after strenuous exercise, [0036] supports muscle maintenance in elderly, [0037] supports muscle maintenance in Duchenne muscle dystrophy, [0038] supports muscle maintenance in inflammatory muscle wasting conditions.” Per Applicant’s claim 2, the above relate at least to skeletal muscle. Per Applicant’s claim 6, the exercise includes resistance exercise, etc. ([0005]).
The Examiner further notes at least the following relevant sections of Liu: “The pharmaceutical and nutraceutical compositions comprising hydroxytyrosol useful for conditions characterized by altered muscle differentiation especially under inflammatory conditions, such as delayed onset muscle soreness subsequent to strenuous exercise or sarcopenia are provided.” (Abstract). “[0001] This invention is related to the use of hydroxytyrosol ("HT"), or an olive juice extract containing hydroxytyrosol as an agent to improve muscle differentiation and thus improve or maintain the body's adaptation to exercise. It also relates to pharmaceutical and nutraceutical compositions useful for conditions characterized by altered muscle differentiation especially under inflammatory conditions, such as delayed onset muscle soreness subsequent to strenuous exercise or sarcopenia.”
[0004] Muscle differentiation is required for maintenance of the skeletal musculature, for wound healing after surgery, trauma or strenuous exercise. Moreover, the formation of new muscle fibers (myotubes) is required for muscle growth.
[0005] Improving or maintaining muscle differentiation is needed e.g. for adaptation to exercise, especially to resistance exercise, and thus is important for sports performance. Muscle differentiation is also needed for mobility and all associated aspects of health, ability to work, and to lead an active life style.
[0006] Improved muscle differentiation is a particular need of elite athletes, whose professional success depends on an optimized training regimen to be able to perform at top level at times of important competitions. Moreover, healthy muscle differentiation is of interest for life style athletes (recreationally active people, weekend warriors), who harness important experiences of fun and satisfaction from successful exercise performance. Women, who in general have a lower muscle mass than men, often are concerned about their physical capabilities, hence are in need of good muscle differentiation.
[0007] A successful training regimen strives to optimize adaptation of the body to exercise. Adaptation to exercise among others includes an increase in aerobic exercise capacity, increased lipid storage especially in oxidative muscle fibers, activation of the endogenous antioxidant defense system, increased vascularization of the musculature, increased erythropoiesis, synthesis of contractile fibers within muscle cells such as actin and myosin and others, and the recruitment of satellite cells to differentiate and fuse into myotubes.
[0008] Oxidative stress induced by exercise is thought to be causally involved in inducing adaptation to exercise, i.e. successful training. The reactive oxygen species are generated during muscle contractions, but also during aerobic energy metabolism (oxidative phosphorylation, oxphos, aerobic respiration). The redox-sensitive MAPK and NFkB signaling pathways and the resulting reactions of cellular stress and inflammation are regarded as important pathways mediating adaptation to exercise (reviewed in Li Li Ji, Free Radical Biology & Medicine 44 (2008), 142-152, Li Li Ji Exp Gerontology 42 (2007), 582-593). In line with this, intervention studies with the antioxidants allopurinol and vitamin C in animal models and in humans have found that antioxidant supplementation reduced adaptation to exercise (Gomez-Carbrera et al. 2005 J Physiol 567, 113-120, Gomez-Carbrera et al. 2008 Am. J. Clin. Nutr. 87(1):142-149, Ristow et al (2009) PNAS 106, 8665-8670).
([0004]- [0008]; emphasis added).
As an additional example showing teaching improving of muscle fatigue or weakness from exercise in Liu, the Examiner notes the endurance exercise procedure experiment in rats.
Endurance Exercise Procedure
[0085] Rats were randomly divided into four groups: Sedentary, Sedentary with HT supplement (25 mg/kg/day), Endurance exercise and Endurance exercise with HT supplement (25 mg/kg/day). HT was administrated by gavage 45 min before exercise program for each animal. Rats were run on a motorized treadmill at a speed of 20 m/min and a grade of 5.degree. for 1 hour per day and 6 days per week. After 8 weeks exercise, endurance capacity was measured by treadmill running to exhaustion at a speed of 30 m/min and a grade of 5.degree.. Exhaustion was defined as the inability to maintain running and avoid sound and light irritation.
Isolation of Skeletal Muscle Mitochondria
[0086] The soleus muscle was removed from each leg. A first portion was frozen in liquid N.sub.2 and used for total RNA and protein extraction. A second portion was used immediately for mitochondrial isolation. Soleus muscles were trimmed off fat and connective tissue, chopped finely with a pair of scissors, and used for mitochondrial isolation.
[. . .]
LTE (Long Term Exercise) on Endurance Capacity and Muscle Atrophy and the Effect of HT Supplement
[0092] We performed a LTE program with rats and studied the effects of HT supplement on physical performance and the underlying mechanism of mitochondrial dynamics. We showed that LTE was prone to reduce endurance capacity, and HT supplement was sufficient to improve endurance capacity of exercise rats by 35% without any effect on sedentary rats (FIG. 9A).”
Accordingly, it would have been obvious to a person of skill in the art before the effective filing date of the claimed invention to optimize the time period of exercise, its intensity and duration relative to the administration of oleuropein or a metabolite thereof, as per Applicant’s claims, based on the disclosure of Liu. The skilled artisan would have been motivated to do so since Liu specifically discloses optimizing the exercise regimen taking into account various specifically enumerated considerations, and further in view of the need to intake a dietary supplement comprising oleuropein or a metabolite thereof so as to further optimize the process of muscle differentiation.
Timing of administration impacts drug pharmacokinetics, and is therefore a result- effective variable, which is subject to optimization. See MPEP 2144.05.
B.There is a Motivation to Optimize Result-Effective Variables
In In re Antonie, 559 F.2d 618, 195 USPQ 6 (CCPA 1977), the CCPA held that a particular parameter must first be recognized as a result-effective variable, i.e., a variable which achieves a recognized result, before the determination of the optimum or workable ranges of said variable might be characterized as routine experimentation, because “obvious to try” is not a valid rationale for an obviousness finding. In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that “obvious to try” was a valid rationale for an obviousness finding, for example, when there is a “design need” or “market demand” and there are a “finite number” of solutions. 550 U.S. at 421 (“The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was ‘[o]bvious to try.’ ... When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under §103.”). Thus, after KSR, the presence of a known result-effective variable would be one, but not the only, motivation for a personal of ordinary skill in the art to experiment to reach another workable product or process.
Therefore, a prima facie case of obviousness has been properly made. Applicant has failed to rebut it, with either argument, or data. For instance, there is nothing of record to show any criticality of Applicant’s claimed timing of administration. There is a sole paragraph in Applicant’s specification, devoid of any further data whatsoever, which simply just generally states that administering close to the time of exercise is selected.
“[0006] In an embodiment, the at least one of oleuropein or metabolite thereof is administered in at least one dose during at least one time period selected from the group consisting of (i) a pre-exercise time between one hour prior to initiation of the exercise and one second prior to the initiation of the exercise, such as between thirty minutes prior to the initiation of the exercise and one minute prior to the initiation of the exercise, (ii) an exercise time between the initiation of the exercise to conclusion of the exercise, and (i) a post-exercise time between one second after the conclusion of the exercise and one hour after the conclusion of the exercise, such as between one minute after the conclusion of the exercise and thirty minutes after the conclusion of the exercise.”
It is noted that administering an energy supplement close to the time when energy is needed is indeed obvious and subject to optimization. Generally, it is not inventive to discover such regimens by routine experimentation when the general conditions of a claim are disclosed in the prior art. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) and MPEP §2144.05(11). The medical arts recognize that drug therapy may be optimized by designing regimens that account for the concentration of a drug, for example, to achieve a desired pharmacological response. The factual underpinnings for doing so are further found in references of record, as well as supported by well-established precedent on optimization.
Accordingly, Liu discloses Applicant’s claimed method. As the Federal Circuit holds, the elements must be arranged as required by the claim, but this is not an ipsissimis verbis test, i.e., identity of terminology is not required. In re Bond, 910 F.2d 831, 15 USPQ2d 1566 (Fed. Cir. 1990). See also MPEP 2131.
Per Liu, administration may be as a “dietary supplement”, which denotes a product taken by mouth that contains a compound or mixture of compounds intended to supplement the diet. The compound or mixture of compounds in these products may include, e.g. minerals. ([0062]). Although Liu does not specifically disclose calcium, it is noted that the term mineral, to include in a dietary supplement, is understood to include calcium. Liu further discloses that the nutraceutical compositions according to the present invention may be in any form that is suitable for administrating to the animal body including the human body, especially in any form that is conventional for oral administration, e.g. in solid form such as (additives/supplements for) food or feed, food or feed premix, tablets, pills, granules, dragees, capsules, and effervescent formulations such as powders and tablets, or in liquid form such as solutions, emulsions or suspensions as e.g. beverages, pastes and oily suspensions, and may comprise other ingredients, e.g. sugar, fat, etc. ([0063]). Liu further discloses administering every day for 1 month, and a sports supplement with a daily dose (Example 3).
Accordingly, it would have been obvious to a person of skill in the art before the effective filing date of the claimed invention to combine the teachings of co-pending application and Liu in order to practice Applicant’s claimed invention with a reasonable expectation of success. The skilled artisan would have been motivated to do so since a method of achieving at least one result selected from the group consisting of . . . (iv) improvement in at least one of muscle functionality, muscle performance, or muscle strength, (v) decreased muscle fatigue, (vi) increased mobility and (vii) treatment of a muscle disorder linked to calcium depletion or deficiency is broadly inclusive of a method of preventing or treating muscle fatigue from exercise and/or for resistance to muscle fatigue from exercise. Further motivation to do so is in view of Liu, which explicitly discloses that the improvement of musculoskeletal benefits specifically extend to exercise and training benefits. Moreover, motivation to do so is found in the art in view of the disclosure of a similar method of formulating the compositions, such as nutritional compositions, dietary supplements, etc.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Other relevant art
The Examiner also restates for the record the following relevant art over which no rejections were made solely in view of its cumulative nature.
-Fujiwara et al., Oleuropein improves insulin resistance in skeletal muscle by promoting the translocation of GLUT4, J Clin Biochem Nutr. 2017 Nov;61(3):196-202
“As the beneficial effects of the Mediterranean diet on human health are well established, the phenolic compounds in olive oil have been gaining interest. Oleuropein, a major phenolic compound in olives, is known to reduce the blood glucose levels in alloxan-induced diabetic rats and rabbits, however, its effect on type 2 diabetes caused by obesity is not clear. The purpose of this study is clarifying the effect of oleuropein on the glucose tolerance in skeletal muscle under the condition of lipotoxicity caused by type 2 diabetes. Oleuropein enhanced glucose uptake in C2C12 cells without insulin. Translocation of glucose transporter 4 (GLUT4) into the cell membrane was promoted by activation of adenosine monophosphate-activated protein kinase (AMPK) but not protein kinase B (Akt). Physiological concentration of oleuropein (10 µM) was sufficient to express beneficial effects on C2C12 cells. Oleuropein prevented palmitic acid-induced myocellular insulin resistance. Furthermore, in gastrocnemius muscles of mice fed a high fat diet, oleuropein also induced the GLUT4 localization into cell membrane. These results suggest the possibility of oleuropein to be effective for type 2 diabetes by reducing insulin resistance in skeletal muscles.” (Abstract)
“Poudyal et al.(21) reported that olive leaf extracts contain polyphenols such as oleuropein and its major metabolite, hydroxytyrosol, which ameliorate the cardiovascular, hepatic, and metabolic symptoms in rat models with obesity and diabetes induced by high-carbohydrate and high-fat diets (HFD). Olive leaf extracts were reported to lower blood cholesterol(22) and lipid concentrations(23) in cholesterol-fed rats.”
“Oleuropein is known to partially metabolize to tyrsol and hydroxyltyrosol.(38) These metabolites possess stronger anti-oxidative activity than oleuropein.(39)”
-Doehner et al., Skeletal muscle weakness is related to insulin resistance in patients with chronic heart failure, ESC Heart Fail, 2015 Jun;2(2):85-89
Background: Chronic heart failure (CHF) is associated with insulin resistance, indicating impairment in the control of energy metabolism. Insulin resistance in CHF relates to symptomatic status and independently predicts poor prognosis. We sought to determine whether insulin sensitivity is related to skeletal muscle strength in patients with CHF, taking into account muscle size and perfusion . . . Conclusions: The myofibril contractile function of the quadriceps, i.e. functional quality of skeletal muscle, is strongly related to insulin sensitivity in patients with CHF and in healthy controls, independently of muscle size. Therapies aimed at improving insulin sensitivity in patients with CHF may clarify whether this relationship is causal. (Abstract).
-WO 2020/229539 A1 to De Marchi et al. (“De Marchi”).
De Marchi generally relates to compositions and methods that use a combination of calcium and at least one of oleuropein or metabolite thereof. More specifically, the present disclosure relates to compositions and methods that increase bioenergetics and mitochondrial function through a combination of calcium and at least one of oleuropein or metabolite thereof to boost mitochondrial calcium import, which in turn can increase muscle contraction and muscle performance to thereby improve, maintain or reduce loss of muscle functionality. ([0001]). One of skill in the art would understand that improve, maintain or reduce loss of muscle functionality would result in improving resistance to muscle fatigue from exercise. To that end, De Marchi very specifically also discloses that muscle fatigue is improved, as is overall muscle performance and muscle strength. “[0015] In another embodiment, the present disclosure provides a method of treating in an individual in need thereof or preventing in an individual at risk thereof (e.g., reducing incidence and/or severity) at least one condition selected from the group consisting of (i) impairment in at least one of muscle functionality, muscle performance, or muscle strength, (ii) muscle fatigue or muscle weakness, (iii) pre-frailty, frailty, sarcopenia or impaired mobility, and (iv) a muscle disorder linked to calcium depletion or deficiency. The method comprises orally administering to the individual in need thereof or at risk thereof an effective amount of a combination of calcium and at least one of oleuropein or metabolite thereof.” “[0019] In another embodiment, the present disclosure provides a method of making a composition for achieving at least one result selected from the group consisting of (i) improved mitochondrial calcium uptake in muscle cells, (ii) improved utilization of calcium in muscle cells, (iii) increased mitochondrial energy in muscle cells, (iv) improvement in at least one of muscle functionality, muscle performance, or muscle strength, (v) decreased muscle fatigue or muscle weakness, (vi) increased mobility and (vii) treatment or prevention of a muscle disorder linked to calcium depletion or deficiency (e.g., reduction in incidence and/or severity). The method comprises adding an effective amount of a combination of calcium and at least one of oleuropein or metabolite thereof to at least one ingredient selected from the group consisting of protein, carbohydrate, and fat.”
To that end, De Marchi very specifically discloses that the claimed method is applied in the context of exercise, and that it includes sports-type resistance exercise and endurance exercise.
[0058] As used herein, a“sportsman” is an individual who participates in at least one of 1) resistance exercise, 2) anaerobic or repeated sprint-type exercise, or 3) endurance exercise.
[0059] Resistance exercise is when a subject undertakes explosive movements of weight, with long periods of rest, and is primarily driven by the phosphocreatine and glycolytic energy systems. Resistance exercise can produce energy quickly, but the subject fatigues quickly. The primary adaptations include increases in muscle mass (hypertrophy) by increased muscle cross-section area through repeated weight lifting training. Hakkinen K. 1989. Neuromuscular and hormonal adaptations during strength and power training. J. Sports Med. Phys. Fitness. 29:9-26; and Hakkinen K. et. al. 1987. Relationships between training volume, physical performance capacity, and serum hormone concentrations during prolonged training in elite weight lifters. Int. J. Sports Med. 8 Suppl 1 :61-65.
[0060] Repeated sprint-type training is anaerobic, involves high-intensity exercise with limited recovery periods, and involves nearly purely carbohydrate metabolism with a large breakdown in muscle glycogen (glycolytic energy production). During these situations of anaerobic energy production, such as high intensity speed training or sports involving repeated sprints, the increased load on the muscles is accomplished by an increased firing of Type Ila fibers. Finally, at very high workloads, type nb glycolytic muscle fibers become activated to maintain the high demand of energy provision via anaerobic energy provision. However, during these situations, the high rate of anaerobic energy production exceeds the rate at which it can be oxidized aerobically within the mitochondria, and this leads to the extreme levels of lactate production found in these types of training situations. Spriet L L, Howlett R A, and Heigenhauser G J. 2000. An enzymatic approach to lactate production in human skeletal muscle during exercise. Med. Sci. Sports Exerc. 32: 756-763.
[0061] Endurance training is characterized by individuals performing low-intensity training over prolonged periods (e.g., >15 minutes). The energy system represented for endurance training includes the aerobic system, which primarily uses aerobic metabolism of fats and carbohydrates to produce the required energy within the mitochondria when ample oxygen is present. The primary adaptations include increased muscle glycogen stores and glycogen sparing at sub-maximal workloads via increased fat oxidation, enhanced lactate kinetics and morphological alterations, including greater type I fiber per muscle area, and increased capillary and mitochondrial density. Holloszy J O, and Coyle E F. 1984. Adaptations of skeletal muscle to endurance exercise and their metabolic consequences. J. Appl. Physiol. 56: 831 -838; and Holloszy J O, Rennie M J, Hickson R C, Conlee R K, and Hagberg J M. 1977. Physiological consequences of the biochemical adaptations to endurance exercise. Ann. N.Y. Acad. Sci. 301 : 440-450.
Accordingly, De Marchi discloses Applicant’s claimed method. As the Federal Circuit holds, the elements must be arranged as required by the claim, but this is not an ipsissimis verbis test, i.e., identity of terminology is not required. In re Bond, 910 F.2d 831, 15 USPQ2d 1566 (Fed. Cir. 1990). See also MPEP 2131.
Per De Marchi, the combination of calcium and at least one of oleuropein or metabolite thereof can be administered to a sportsman before, during and/or after exercise, for example less than two hours before the exercise or less than one hour before the exercise and less than two hours after the exercise or less than one hour after the exercise. ([0077]). A “sportsman” is defined as an individual who participates in at least one of 1) resistance exercise, 2) anaerobic or repeated sprint-type exercise, or 3) endurance exercise. ([0058]). Claim 5 recites that the metabolite of oleuropein is selected from the group consisting of oleuropein aglycone, hydroxytyrosol, homovanillyl alcohol, isohomovanillyl alcohol, glucuronidated forms thereof, sulfated forms thereof, derivatives thereof, and mixtures thereof. The method comprising orally administering to an individual an effective amount of a combination of calcium and at least one of oleuropein or metabolite thereof (claim 1, to include in a food product further comprising a component selected from the group consisting of protein, carbohydrate, fat and mixtures thereof (claim 9).
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/SVETLANA M IVANOVA/ Primary Examiner, Art Unit 1627
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