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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 09/10/2026 has been entered.
Status of Claims
Claims 1-7, 9-18 and 20 and are pending following the Reply filed 09/10/2026. Claims 8 and 19 have been cancelled. Claims 1, 10-12 and 20 have been amended without introducing new matter. All pending claims have been examined on the merits.
Withdrawn
Any objection or rejection of claims 8 or 19 is moot because the claims have been cancelled.
The objections to claim 10-11 are withdrawn in light of the amendments.
The rejections under 35 U.S.C. 112(b) are withdrawn in light of the amendments.
The written description rejection of claims 1-7, 9-12, 14-18 and 20 under 35 U.S.C. 112(a) is withdrawn in light of the amendments. In particular, these claims now require the microorganism for culturing to be a genetically modified Saccharomyces cerevisiae which has support in the specification. However, this rejection is maintained for independent claim 13. See the present rejection below and Response to Arguments for further discussion.
Claim Rejections - 35 USC § 112(a)—Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 13 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Brief Statement of the Issue(s)
The claim is directed to microorganisms capable of producing retinol in the presence of carnosic acid, wherein the specification fails to permit an ordinary artisan to envisage which microorganisms are capable of providing retinol and also fails to adequately disclose which microorganisms can do so without being inhibited by the presence of carnosic acid in culture. Furthermore, it is unknown what concentrations of carnosic acid can be used for any given microorganism when producing retinol, and the specification does not provide sufficient exemplification or relevant structure/function teachings to show possession of this broad genus of microorganisms for producing retinol.
Claim Scope
Claims 13 is representative of the pending claim scope and recites a method for preparing retinol compositions, wherein carnosic acid is added to a culture medium comprising a microorganism which is only defined as being “capable of providing retinol”.
As the “microorganism” of the present invention is only defined as “being capable of providing retinol”, it is unclear if the claim scope encompasses trillions of species or perhaps only a few in view of the functional limitations set forth in the claim(s). Accordingly, the claim scope reasonably appears to be vast and highly varied.
Actual Reduction to Practice
The examples of Applicant’s disclosure involve: (1) preparing a composition comprising sunflower oil, hydro-ethanolic rosemary extract, (2) adjusting the carnosic acid content of the mixture by the addition of oil, and (3) assessing the compositions at 1, 3 and 6 months to ascertain if retinol oxidation had occurred (see pg. 23, “Example” 1 & 2). Hence, the only reduction to practice did not include any microorganism or any process step of culturing said microorganism. Conversely, Applicant’s examples were merely used to demonstrate the effect of carnosic acid in preventing the oxidation of retinol. Accordingly, zero examples of the claimed invention were reduced to actual practice.
Assessment of whether disclosed species are representative of the claimed genus
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus (see, e.g., MPEP § 2163(II)(3)(a), MPEP §2163.03(V)). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In this case, the claims encompass an essentially infinite number of microorganisms, but zero were reduced to practice.
Although the MPEP does not define what constitutes a sufficient number of representative species, the Courts have indicated that the disclosure of two species within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618. Similarly, the disclosure of zero species of the claimed invention does not provide sufficient disclosure to satisfy the written description requirement for the instantly claimed genus.
Identifying characteristics of the genus
In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
The specification as filed states: (1) the nature of the microorganism is not limited as long as it is a microorganism capable of producing retinol, (2) the microorganism may be Yarrowia lipolytica or Saccharomyces cerevisiae, (3) the microorganism may be genetically modified to optimize the production retinol, and (4) “[e]xamples of suitable microorganisms are described in US 2022/017878 A1, the disclosure of which in this context is herewith incorporated by reference” (see pg. 9, lines 11-15). The specification also states that the potential toxicity of carnosic acid to the microorganism can be determined by testing the effect of different concentrations of carnosic acid on the microorganism during the culturing phase, and that such testing is routine work for the skilled person (see pg. 8, lines 8-10).
The inventors of the recited reference, Yu et al. (US 2022/017878 A1; cited in the IDS filed 08/08/2023; hereafter, “Yu”), disclose a microorganism for producing retinol, wherein certain protein activities were enhanced (see pg. 1, para. [0005]). Similar to the present disclosure, Yu discloses that the “microorganism of the present invention is not limited, as long as it is a microorganism having an ability to produce retinol” and “may be Yarrowia lipolytica or Saccharomyces cerevisiae” (see pg. 6, para. [0064]). In Yu’s examples, Saccharomyces cerevisiae, a yeast strain widely used in recombinant protein production, was selected as a strain for producing retinol (see pg. 7, para. [0083]), but to prepare the strain for producing retinol, high-efficiency gene manipulation in this strain was required (see pg. 7, para. [0084]). Yu teaches the design of a GGPP-to-retinol metabolic pathway (GGPP[Wingdings font/0xE0]phytoene[Wingdings font/0xE0]
neurosporene[Wingdings font/0xE0]lycopene[Wingdings font/0xE0]β-carotene[Wingdings font/0xE0]retinal[Wingdings font/0xE0]retinol) which required nucleotide sequences encoding several heterologous genes (derived from other species) in this pathway to be synthesized for transforming the S. cerevisiae strain (see pg. 7, paras. [0086]-[0087]; pg. 8, para. [0092] and [0094]).
Zero discussion is provided in the originally filed disclosure identifying which other species are amenable to these genetic transformations or what other modifications would be required for these other species to produce retinol in a culture medium, particularly in the presence of carnosic acid. It would not be apparent to any skilled artisan, based on the disclosure of two genetically modified yeast strains, which culturable microorganisms (gram-positive bacteria, gram-negative bacteria, yeasts, non-yeast fungi, non-fungi eukaryotes, archaebacteria, etc.) are not only capable of being transformed by the methods taught by Yu, but can also be cultured in the presence of carnosic acid without toxic effects. It should be noted that while the specification states the potential toxicity of carnosic acid to the microorganism can be routinely determined, the written description requirement requires that the specification clearly shows that the inventor actually possessed the full scope of the claimed invention, which is not a matter pertaining to the amount of experimentation, but the sufficient disclosure of shared structural characteristics.
Accordingly, the functional limitation of “capable of providing retinol” is only utilized as a vague attempt to capture unknown and undisclosed structures, sufficient to achieve some functional result desired for the disclosed invention to achieve. However, the disclosure does not meaningfully disclose an unambiguous structure/function relationship permitting an artisan to identify, a priori, which exact structures do or do not satisfy the functional limitations at issue.
Predictability in the Art
According to Birtić et al. (cited in the IDS filed 08/08/2023; hereafter, “Birtic”), carnosic acid (salvin) possesses antioxidative and antimicrobial properties with potential applications within the food, nutritional health and cosmetics industries, but there is a deficiency in our current understanding of its relevant biochemical properties (see Abstract). Birtic discloses: (1) rosemary extracts rich in carnosic acid have been shown to have antimicrobial activity, (2) studies on various pathogens suggest that carnosic acid was the most active compound involved in this activity, (3) among 8 major rosemary phenolics, carnosic acid was shown to have the strongest antilisterial activity, (4) both Gram positive bacteria (e.g., Bacillus, Enterococcus, Streptococcus, Staphylococcus) and Gram negative bacteria (e.g., Escherichia, Salmonella, Campylobacter) are responsive to carnosic acid (see pg. 14, col. 1, para. 5 to col. 2, para. 1). Birtic teaches that while mechanisms involved in antimicrobial activities of phenolic diterpenes have not yet been elucidated, it has been suggested that the lipophilic structure of these compounds allows them to insert into the bacterial membrane (see pg. 14, col. 2, para. 1). According to Oreopoulou et al. (previously cited), the constituents of rosemary extracts, including carnosic acid and carnosol, have been associated with several antifungal and antimicrobial effects (see pg. 4, para. 2).
Similar to Yu’s disclosure, Kim et al. (US Patent No. 9,644,217 B2; previously cited) teach a method for producing retinoids from a microorganism (see Abstract), wherein the microorganism is of the genus Escherichia and may either be a laboratory strain that already produces retinoids (Escherichia coli strains DH5-alpha, MG1655, BL21, S17-1, XL1-Blue, BW25113) or one that has been transformed by genes associated with one or more retinoid syntheses pathways (see col. 2, lines 29-31, 50-56).
Hence, the prior art teaches that retinol production has been achieved in certain laboratory strains of yeast and E. coli by the careful manipulation of certain known genetic structures that collectively form one of several metabolic pathways that can be used to transform the microorganism to produce retinol. However, it would be apparent to a skilled artisan that the selection of these transformations are dependent on which metabolic genes in these pathways are already present or not present in the microorganism, and they would not be able to immediately envisage which strains can be transformed with which genes in order to produce retinol in a culture medium containing carnosic acid. Furthermore, a person of ordinary skill would not be able to immediately envisage what amounts of carnosic acid content in the culture medium would not be toxic for each and every possible member of this genus. This is a particular problem, because while the prior art teaches carnosic acid to have antioxidant effects, it also teaches it to have antimicrobial and antifungal effects and is otherwise silent on the use of carnosic acid in microbial culture media.
Although the level of skill in the art is high, the predictability in the art is low due to the complexity of biological systems and the lack of relevant teachings on using carnosic acid in culture media. Specifically, an artisan would not be able to predict or identify, a priori, and in the absence of any guidance or consensus structures exactly what microorganisms would be capable of providing retinol in a culture medium containing carnosic acid.
Accordingly, in the absence of sufficient structure/function teachings identifying particular microbial strains capable of providing retinol in the presence of carnosic acid, as required to practice the full scope of the claims, an artisan would not reasonably conclude that Applicant possessed the full scope of the broad and highly varied claim scope.
Conclusion
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). The courts have stated that “merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus” (see, e.g., AbbVie v. Janssen, 111 USPQ2d 1780 (Fed. Cir. 2014) at 1789). In addition, the Courts have stated
“[r]egardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
This is pertinent because, in the instant case, Applicants have claimed a broad and highly varied genus comprising an unknown number of species defined by reference to one or more functional limitations; however, the originally filed disclosure has failed to identify any common structure/function relationship sufficient to permit an artisan to identify what structures are included or excluded by the claim scope. This also means that the skilled artisan cannot envisage what structures infringe or do not infringe upon the pending claim scope.
In conclusion, for the reasons discussed above, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention.
Claim Rejections - 35 USC § 103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-7, 10-18 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Yu et al. (US 20220017878 A1; effectively filed 11/30/2018; cited in the IDS filed 08/08/2023), hereafter “Yu”, and further in view of Maiza et al. (cited in the IDS filed 08/08/2023), hereafter “Maiza”.
Regarding claim 1, Yu teaches a method of producing retinol, comprising culturing a microorganism, wherein the microorganism has an improved ability to produce retinal (see Abstract). Yu teaches retinol is a high-value-added raw material that has anti-wrinkle and antioxidant effects (see pg. 1, para. [0002]), but, despite its usefulness, production of retinol is not easy and has high production costs (see pg. 1, para. [0003]). Yu discloses the development of a microorganism capable of more stably producing retinol with high efficiency (see pg. 1, para. [0004]). Yu teaches the culture medium used for culturing the microorganism for producing retinol may contain oils and fats as a carbon source, such as “soybean oil, sunflower seed oil, peanut oil, and coconut oil” (see pg. 6, para. [0073]). Hence, Yu teaches a process of preparing a composition comprising retinol, the process comprising the step of culturing a microorganism capable of providing retinol in a culture medium comprising oil. As Yu teaches oil to be present in the culture medium, the composition produced by the method comprises retinol and oil.
In Yu’s examples, Saccharomyces cerevisiae, a yeast strain widely used in recombinant protein production, was selected as a strain for producing retinol (see pg. 7, para. [0083]), but to prepare the strain for producing retinol, high-efficiency gene manipulation in this strain was required (see pg. 7, para. [0084]). Yu teaches the design of a GGPP-to-retinol metabolic pathway (GGPP[Wingdings font/0xE0]phytoene[Wingdings font/0xE0]neurosporene[Wingdings font/0xE0]lycopene[Wingdings font/0xE0]β-carotene[Wingdings font/0xE0]retinal[Wingdings font/0xE0]retinol) which required nucleotide sequences encoding several heterologous genes in this pathway to be synthesized for transforming the S. cerevisiae strain (see pg. 7, paras. [0086]-[0087]; pg. 8, para. [0092] and [0094]). Therefore, Yu teaches the microorganism is a genetically modified Saccharomyces cerevisiae modified to optimize the production of retinol.
Yu does not teach the process wherein carnosic acid is added to the culture medium.
Maiza’s study aims to characterize the effects of aromatic plants (rosemary and clove) on the nutritional, volatile and oxidative profile of cow ghee (see Abstract). Maiza teaches that one of the most widespread and well-known properties of ghee is its wound healing activity, due to its valuable content of fat-soluble vitamins, such as vitamin A (see pg. 8910, col. 1, para. 4). However, due to its high lipid content, ghee undergoes rapid auto-oxidation with a reduction of its shelf-life, which may be solved by adding antioxidants into ghee (see pg. 8910, col. 1, para. 4-5). Maiza teaches that due to their high content in phenolic compounds, rosemary and clove leaves are characterized by an important antioxidant activity, and can be used as plant extracts to prevent lipid oxidation in oily products (see pg. 8910, col. 2, para. 2). Maiza’s study evaluated the effect of plant enrichment on the vitamin composition of ghee; notably, the retinol content of the different ghee samples analyzed after 21 days showed that the highest level of retinol was observed in rosemary enriched ghee (see pg. 8913, col. 2, para. 3). Maiza teaches that rosemary-enriched samples showed higher levels of targeted phenolic compounds, the major compound present in all samples being carnosic acid (see pg. 8914, col. 1, para. 2). Maiza teaches that polyphenols contained in rosemary are released into the ghee matrix, increasing its oxidative stability (see pg. 8914, col. 2, para. 2). Maiza teaches that the results of this study suggest that ghee could be useful for skincare, especially when it is enriched with natural antioxidants from rosemary leaves (see pg. 8917, col. 1, para. 1).
In summary, Maiza teaches that rosemary extracts containing high carnosic acid content provide antioxidant effects to fat-soluble vitamins, such as vitamin A (i.e., retinol), and suggests that the retinol content of oily compositions can be significantly enhanced and preserved in the presence polyphenols, specifically carnosic acid, derived from rosemary.
The examiner notes that the claim does not limit the timing of when the carnosic acid is added to the medium or the amount of carnosic acid that is added. The scope of the claim also includes adding this ingredient in a non-toxic amount (see instant claim 3), which would itself only require a routine amount of effort to determine (see instant specification at pg. 8, lines 8-10). Furthermore, Yu teaches the method of producing retinol may further include the step of recovering retinol from the medium using an appropriate method known in the art (see pg. 7, para. [0081]), wherein the term “medium” refers to both the culture medium for culturing the microorganism and the product obtained after culturing the same (see pg. 6, para. [0072]). Therefore, a person of skill would have also recognized that the carnosic acid could be added to the medium at a later stage of the process, wherein the viability of the microorganism is no longer required, or has already been separated from the medium, in order to obtain a product comprising the retinol in a preserved state, as suggested by Maiza.
It would have been obvious at the time of filling for a person of ordinary skill in the art to have arrived at the claimed invention by combining the teachings of Yu and Maiza, because both references teach the use of compositions comprising retinol for skincare applications. One would have recognized from Maiza’s disclosure that polyphenols derived from rosemary, particularly carnosic acid, may be useful in preserving retinol due to its antioxidants effects. One would have also recognized that Yu teaches the use of oils in a culture medium to bio-produce retinol, while Maiza teaches the solution of using rosemary-derived polyphenols to stabilize the lipid oxidation of retinol in oily compositions. One would have been particularly motivated to combine these teachings, because Yu teaches an improved method for producing retinol, while Maiza teaches an effective means to overcome the limited shelf-life of compositions containing retinol. As the microorganism of Yu’s disclosure produces retinol in a culture medium, it would have been obvious in view of Maiza to have added carnosic acid to the medium in a non-toxic amount or at a later stage of the process to protect the retinol from oxidation. As Maiza teaches carnosic acid is the major phenolic compound of rosemary extract, which was demonstrated to increase retinol content in the samples of Maiza’s study, a person of ordinary skill would have recognized the results of the combination to be predictable with a reasonable expectation of success. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Regarding claim 2, Yu teaches the method of producing retinol by culturing a microorganism in a culture medium comprising oils, as discussed above. As Maiza teaches carnosic acid to effectively preserve retinol by preventing oxidation, it would have been obvious to have added the carnosic acid to the culture medium at any time to preserve the retinol being produced. As previously noted, a person of skill could have routinely determined an amount of carnosic acid that is not toxic to the microorganism, or added this ingredient at a later stage of culturing, which is within the scope of the claim.
Regarding claim 3, Yu teaches a method to produce retinol by culturing a microorganism that produces retinol. Hence, it would have been obvious to have added carnosic acid in an amount that is not toxic to the microorganism, because the microorganism is required to produce the retinol.
Regarding claim 4, Yu teaches the method may further include the step of recovering retinol from the cultured microorganism or culture medium using an appropriate method known in the art, and the step of recovering retinol may further include a separation process and/or a purification step (see pg. 7, para. [0081]). Furthermore, Maiza teaches retinol is a fat soluble vitamin, and carnosic acid prevents oxidation of retinol, as discussed above. Hence, it would have been obvious to have isolated the composition comprising retinol from the cultured microorganism and/or culture medium while retaining the oil and the carnosic acid.
Regarding claim 5, Maiza teaches the carnosic acid in the form of a rosemary extract, as discussed above. In view of the instant specification (see pg. 2, lines 20-22) and the instant claims (e.g., claim 6), rosemary extract meets the limitation of an extract obtained from at least one plant selected from the Lamiaceae family.
Regarding claim 6, Maiza teaches that the major compound present in all samples analyzed was carnosic acid with levels ranging from 30 to 77 mg/kg (see pg. 8914, col. 1, para. 2) and, specifically, 77.1 mg/kg in the sample using rosemary extract (see pg. 8914, Table 4).
Maiza does not specifically teach an extract obtained or obtainable from rosemary with a carnosic acid content of at least about 20% by weight of the rosemary extract.
However, under the broadest reasonable interpretation of the claim, the further limitation of “wherein… the carnosic acid content in the rosemary extract…is at least about 20% by weight of the rosemary extract” does not specify the amount of carnosic added or rosemary extract added to the culture medium or the final concentration of carnosic acid in the culture medium. This limitation merely states the concentration of carnosic acid in the extract before any addition to the culture medium is made. Accordingly, it would have been prima facie obvious to have added rosemary extract of any carnosic acid concentration to the culture medium to achieve the final concentration taught by Maiza.
Regarding claim 7, Yu teaches the microorganism is cultured in a culture medium comprising soybean oil, as discussed regarding claim 1.
Regarding claim 10, Yu teaches that retinol produced by the method may be used as a cosmetic composition (see pg. 2, para. [0019]). Furthermore, Maiza teaches that the compositions produced in the study could be useful for skincare, especially when they are enriched with natural antioxidants from rosemary (see pg. 8917, col. 1, para. 1). Hence, it would have been obvious to have provided the composition as s a cosmetic composition.
Regarding claim 11, Yu teaches that retinol produced by the method may be used as a cosmetic composition, and Maiza teaches that the compositions produced in the study could be useful for skincare, especially when they are enriched with natural antioxidants from rosemary, as discussed regarding claim 10. Hence, it would have been obvious to have incorporated the composition into a product.
Regarding claim 12, Yu teaches that retinol produced by the method may be used as a cosmetic composition, and Maiza teaches that the compositions produced in the study could be useful for skincare, especially when they are enriched with natural antioxidants from rosemary, as discussed regarding claim 10. Hence, it would have been obvious to have incorporated the composition into a cosmetic product.
Regarding claim 13, Yu teaches a process of preparing a composition comprising retinol, the process comprising the step of culturing a microorganism capable of providing retinol in a culture medium comprising oil, as discussed regarding claim 1. Maiza teaches that rosemary extracts containing high carnosic acid content provide antioxidant effects to fat-soluble vitamins, such as vitamin A (i.e., retinol), and suggests that the retinol content of oily compositions can be significantly enhanced and preserved in the presence polyphenols, particularly carnosic acid, derived from rosemary, as discussed regarding claim 1. Hence, claim 13 is obvious for the same reasons as claim 1.
Regarding claim 14, Maiza teaches carnosic acid is present within an extract obtained from rosemary, as discussed regarding claim 1.
Regarding claim 15, Maiza teaches carnosic acid is present within an extract obtained from rosemary, as discussed regarding claim 1. Yu discloses that the rosemary extract was obtained from dried rosemary leaves (see pg. 8911, col. 1, para. 1).
Regarding claim 16, Maiza teaches that some problems can be linked to the transfer of phenolic compounds (e.g., carnosic acid) from plants to a highly lipophilic matrix, such as butter oil (see pg. 8914, col. 2, para. 2). Maiza teaches that to solve this problem, some studies have used aqueous and ethanolic extracts of plants instead of proper plant leaves for enrichment (see pg. 8914, col. 2, para. 3). Therefore, it would have been obvious to use carnosic acid in the form of a hydro-ethanolic extract, because Maiza teaches this may solve problems associated with transferring carnosic acid into a highly lipophilic matrix (i.e., an oil).
Regarding claim 17, Maiza teaches carnosic acid in the form of an extract obtained from rosemary, as discussed regarding claim 1. Maiza teaches that using aqueous and ethanolic extracts may solve problems associated with transferring carnosic acid into highly lipophilic matrices (i.e., oils), as discussed regarding claim 16. Hence, claim 17 is obvious for the same reasons discussed regarding claims 1 and 16.
Regarding claim 18, Maiza teaches that the major compound present in all samples analyzed was carnosic acid with levels ranging from 30 to 77 mg/kg (see pg. 8914, col. 1, para. 2) and, specifically, 77.1 mg/kg in the sample using rosemary extract (see pg. 8914, Table 4).
Maiza does not explicitly teach an extract obtained or obtainable from rosemary with a carnosic acid content of at least 30% by weight of the rosemary extract.
However, under the broadest reasonable interpretation of the claim, the further limitation of “wherein the carnosic content in the extract…is at least about 30% by weight of the rosemary extract” does not specify the amount of carnosic acid or rosemary extract added to the culture medium or the final concentration of carnosic acid required in the culture medium. This limitation merely states the concentration of carnosic acid in the extract before any addition to the culture medium is made. Accordingly, it would have been prima facie obvious to have added rosemary extract of any carnosic acid concentration to the culture medium to achieve the final concentration taught by Maiza.
Regarding claim 20, Yu teaches that the retinol composition produced by the method has the effects of preventing skin aging, improving skin elasticity, and improving wrinkles (see pg. 2, para. [0019]) which meets the limitation of an “anti-aging product”. Hence, it would have been obvious to have provided the cosmetic product as an anti-aging product.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Yu and Maiza, as applied to claims 1-8 and 10-20 above, and further in view of Kim et al. (US Patent No. 9,644,217; previously cited), hereafter “Kim”.
Regarding claim 9, Yu does not explicitly teach the process is conducted in a bioreactor containing an aqueous phase and an oily extraction phase.
However, Yu teaches that “culturing” refers to growing the microorganism in an appropriately controlled environment, and the culture process may be achieved according to the appropriate culture conditions known in the art. Further, Yu teaches that the step of culturing the microorganism may be performed by a known batch culture method, continuous culture method, fed-batch culture method, etc. See pg. 6, para. [0067]. Yu also teaches that oxygen, nitrogen hydrogen, or carbon dioxide gas may be injected into the culture and provides ranges for aeration rates (see pg. 6, para. [0069]), culture temperatures (para. [0070]), and agitation rates for operation in a “reactor” during culturing (para. [0071]). Hence, it would have been recognized by a person of ordinary skill in the art that the culturing of the microorganism under such controlled conditions in a “reactor” could be accomplished in a “bioreactor” in view of Yu’s disclosure.
Furthermore, Kim teaches a method for producing retinoid from a microorganism, and more specifically, to a method for effectively obtaining retinoid, which lacks stability, from a microorganism by cultivating the microorganism capable of producing retinoid in a medium containing a lipophilic substance, and separating the retinoid from the lipophilic substance (see Abstract). Kim teaches that “retinoids” include retinol (see col. 4, lines 52-56). Kim teaches that retinoids are chemically unstable, easily oxidized, and liable to intracellular oxidative degradation (see col. 1, lines 56-61; col. 7, lines 50-53). Kim teaches the lipophilic substance may include dodecane and/or mineral oil (see col. 6, lines 15-19) and the culturing can take place in a “fermentation tank” (see col. 6, line 40). Kim teaches the culturing may be performed in a culture medium in the presence of a lipophilic substance while placing a dodecane phase formed of a lipophilic substance on the surface of the medium, optionally while the culture is under agitation (see col. 7, lines 24-28). Kim teaches that when a microorganism for producing retinoids is cultured without the lipophilic substance, the production of retinoids may reach a maximum level, and subsequently decrease (see col. 7, lines 46-49), whereas if the microorganism is cultured in the presence of the lipophilic substance, the produced retinoid may be absorbed into the lipophilic phase before being degraded by the cell, thereby improving productivity of retinoid (see col. 7, lines 54-59). Kim teaches the lipophilic substance may be hydrophobic and used for extracting the retinoid (see col. 7, lines 60-63).
In summary, Kim teaches the culturing of a retinol-producing microorganism in a 2-phase culture system wherein the retinol accumulates in a lipophilic, hydrophobic phase (i.e., oil) for later extraction of the retinol from the culture medium.
It would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention, because both Yu and Kim teach methods to produce retinol by culturing microorganisms. One of ordinary skill would have recognized from both references the suggestion to perform culturing in a “reactor” or “fermentation tank” wherein conditions during culturing could be controlled, and one would have further recognized from Kim the advantage of using a lipophilic, hydrophobic phase in the culture medium to capture and extract the produced retinol (i.e., an “oily extraction phase”). Further, one would have been motivated to combine these teachings, because Kim teaches that retinol is unstable and prone to degradation in the presence of the microbial cell, and the oily phase of the culture medium (e.g., dodecane and/or mineral oil) protects the retinol from degradation while providing an effective means for extraction. One would have also recognized that the oxidative instability of retinoids taught by Kim provides further motivation to apply the teachings of Maiza and to have added carnosic acid in the form of a plant extract to reduce oxidation and improve product yield. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Response to Arguments
Regarding the claim rejections under 35 USC 112(a), Applicant argues that the amended claims are believed to amply address and overcome the rejection. Regarding the amendments to the claims (see Remarks at pg. 5), Applicant states that the recited microorganism and its preparation are disclosed in detail in US 2022/017878 A1, which has been cited several times in the present application and the disclosure of which has been incorporated by reference (see e.g. page 2, lines 9-13 of the PCT specification of the instant application). The attention of the Office is also directed to examples 1 and 2 (paragraphs [0083] to [0110] of the application) which describe in detail how the genetically modified Saccharomyces cerevisiae was produced and used for retinol production. Thus, the applicant asserts that the present claims are fully "enabled" by the present application and all objections/ rejections thereto should be withdrawn.
Applicant’s arguments regarding the amendments to claims 1-7, 9-12, 14-18 and 20 with respect to the Written Description rejection under 35 U.S.C. 112(a) have been fully considered and are persuasive. Thus, the rejection of these claims has been withdrawn.
Applicant’s arguments regarding the written description rejection of claim 13 have been fully considered they are not persuasive.
Claim 13 does not depend from any of the amended claims and therefore does not obviate the rejection based solely on the amendments to the claims. Furthermore, the claim was/is rejected for failing the Written Description requirement, which is separate and distinct from the enablement requirement. It should be noted that while the specification states the potential toxicity of carnosic acid to the microorganism can be routinely determined, the written description requirement requires that the specification clearly shows that the inventor actually possessed the full scope of the claimed invention, which is not a matter pertaining to the amount of experimentation, but the sufficient disclosure of shared structural/functional characteristics. In the instant case, claim 13 is still directed to any microorganism capable of producing retinol in a media containing carnosic acid, and the rejection is maintained for the same reasons previously set forth.
Regarding the rejections under 35 U.S.C. 112(d), Applicant states that the amended claims are believed to fully address and overcome the rejections.
Applicant’s arguments have been considered but they are moot, because these rejections were withdrawn in the previous office action.
Regarding the rejections under 35 U.S.C. 103, Applicant argues that the rejection relies upon the benefit of hindsight reasoning, drawing upon the “hindsight knowledge of the patented invention, when the prior art does not contain or suggest that knowledge”. Applicant argues that Maiza does not overcome the shortcomings of Yu, because “Maiza is distinguishable”. Maiza discloses a natural product – ghee – which comprises retinol (vitamin A). However, as it is known that retinol is easily oxidized and may degrade the properties of ghee, including the tase thereof, the solution to this suggested by Maiza is to add further natural materials, either rosemary or clove, as antioxidants the ghee to stabilize the retinol. Maiza is clearly directed to the use of ‘natural’ materials, whereas Yu is to a process for production of retinol. Maiza’s teachings are to improve the properties of ghee, and teaches nothing to any other benefits, nor utility in a biotechnological process such as Yu, and therefore there is no reason for a skilled artisan to look to Maiza to combine it with Yu.
Applicant’s arguments have been fully considered but they are not persuasive.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
As discussed in the rejection, Maiza teaches that rosemary extracts containing high carnosic acid content provide antioxidant effects to fat-soluble vitamins, such as vitamin A (i.e., retinol), and suggests that the retinol content of oily compositions can be significantly enhanced and preserved in the presence of polyphenols, particularly carnosic acid, derived from rosemary. This finding forms the basis for combining the references, which is derived from the prior art itself, not impermissibly drawn from Applicant’s disclosure. Maiza clearly attributes the effects of antioxidant activity, the prevention of lipid oxidation, and increased retinol levels in oily products provided by rosemary extract to be due to its high content of phenolic compounds, the major one being carnosic acid (see Abstract; pg. 8910, col. 2, para. 2; and pg. 8914, col. 1, para. 2). Applicant’s argument fails to specifically point out which specific facts drawn from the prior art references are in error or what facts could have only come from Applicant’s disclosure.
In response to applicant’s argument that Maiza is directed to the use of natural materials to improve the properties of ghee, and teaches nothing to any other benefits, nor utility in a biotechnological process, such as in Yu, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In the instant case, a person of ordinary skill would have recognized that both references relate to methods of developing retinol-containing products, which are useful for their antioxidant effects on the skin, including improving wrinkles. Applicant’s assertion that Maiza is directed to improving “the properties of ghee” using natural materials, is an unreasonably narrow interpretation of Maiza’s disclosure. A person of ordinary skill would have recognized that the active ingredient of the ghee taught by Maiza is retinol, which is the same cosmetic ingredient produced by Yu’s methods, and that the effects of the “natural materials” taught by Maiza, i.e., rosemary extract, are clearly attributed to the presence of carnosic acid and other polyphenolic compounds in the extract.
Applicant further argues that the prior art does not disclose nor suggest that carnosic acid (rosemary) could be included in a culturing medium during the action of the microorganism. In particular, it does not provide any hint that this would not cause any issues with the microorganism's activity, leave alone that this would be beneficial in any way.
Applicant’s arguments have been fully considered but they are not persuasive.
First, the scope of the claims does not exclude adding carnosic acid after completion of the retinol synthesis. Here, the recitation of “wherein carnosic acid is added to the culture medium” is not recited in such a manner as to limit when the carnosic acid is added. Furthermore, in view of the specification: “The oil in the extraction phase, may comprise carnosic acid… or carnosic acid may be added to the oil at an appropriate point” (see pg. 11, lines 25-27). Therefore, the scope of the process, as claimed, would include adding carnosic acid at any appropriate timepoint in order to arrive at a final product (“composition”) comprising retinol, oil, and carnosic acid, including later stages of the process wherein the microorganism’s activity is no longer relevant to said process.
It should also be noted that the scope of the claims do not limit the amount of carnosic acid present in the medium, allowing for even trace amounts to be present during culturing. By Applicant’s own admission, the appropriate concentration can be determined by testing the effect of different concentrations of carnosic acid on the microorganism during the culturing phase, and such testing is routine work for the skilled person (see specification at pg. 8, lines 8-10). Hence, given the information that carnosic acid preserves retinol (as taught by Maiza), a person of skill would have recognized the obvious solution of adding this compound to the product taught by Yu. If it were efficacious to have added the carnosic acid in some concentration at an earlier step in the method, without interfering with the production of retinol, this would have been routinely discovered when optimizing the process.
Conclusion
No claims are allowed.
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/DENNIS IGNATIUS ARMATO JR/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651
