DETAILED ACTION
Status of the Application
Claims 1-16, 18-19, 20-23 are pending.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A preliminary amendment of claim 20, cancellation of claim 17, and addition of claims 21-23 as submitted in a communication filed on 8/7/2026.
Applicant’s election of Group 40, claim 20, directed in part to a method of synthesizing a mogroside that requires the polypeptide of SEQ ID NO: 38, as submitted in a communication filed on 8/7/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)).
New claims 21-23 are directed to the elected invention. Claims 1-16, 18-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/7/2026.
Claims 20-23 are at issue and are being examined herein.
Specification
The first paragraph of the specification is objected to because it does not provide the current status of related applications (e.g., now US Patent No. X). Appropriate correction is required.
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. The claims under consideration are directed to a method. Appropriate correction is required.
Priority
Acknowledgment is made of a claim for domestic priority under 35 U.S.C. 119(e) to provisional application No. 62/089,929 filed on 12/10/2014, and 62/048,924 filed on 09/11/2014.
Acknowledgment is made of a claim for domestic priority under 35 U.S.C. 120 or 121 to US application No. 17/563,127 filed on 12/28/2021 and 15/510,708 filed on 03/13/2017.
Upon a cursory review of the specifications of applications to which this application claims priority, it has been found that SEQ ID NO: 38 was first disclosed in PCT/IL2015/050933 filed on 09/10/2015.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 8/26/2024, 2/26/2025, 6/17/2025, and 3/19/2026 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings submitted on 6/28/2024 have been reviewed and are accepted by the Examiner for examination purposes.
Claim Objections
Claims 21-22 are objected to due to the recitation of “host cell is…a bacteria”. To be grammatically correct, in view of the fact that the term “bacteria” is the plural form of “bacterium”, the term should be amended to recite “host cell is ….a bacterium”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA )
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 20-23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 20 (claims 21-23 dependent thereon) is indefinite in the recitation of “..contacting a uridine …transferase enzyme…having an amino acid sequence of SEQ ID NO: 38 or at least 90% identical to SEQ ID NO: 38 ….wherein said contacting is performed in a host cell heterologously expressing the polypeptide of SEQ ID NO: 38 or a lysate of said host cell” for the following reasons. It is unclear as to how one could practice the contacting with an enzyme that has at least 90% sequence identity with the polypeptide of SEQ ID NO: 38 when the cell only expresses an enzyme that has SEQ ID NO: 38. Also, it is unclear if the enzyme is partially required to comprise SEQ ID NO: 38 or if the enzyme is partially required to comprise a fragment of SEQ ID NO: 38 in view of the recitation of “an amino acid sequence of SEQ ID NO: 38”. The term “an amino acid sequence of SEQ ID NO: 38” can be interpreted as a fragment within SEQ ID NO: 38. For examination purposes, it will be assumed that the claims require in part a UGT that comprises an amino acid sequence at least 90% sequence identical to the polypeptide of SEQ ID NO: 38 and a host cell that expresses a UGT that comprises an amino acid sequence at least 90% sequence identical to the polypeptide of SEQ ID NO: 38. Correction is required.
Claim 21 is indefinite in the recitation of “host cell is a yeast cell, a bacteria and a plant cell” for the following reasons. It is unclear as to how a host cell can be a yeast cell, a bacterium and a plant cell all at the same time. If the intended limitation is “host cell is a yeast cell, a bacterium or a plant cell”, the claim should be amended accordingly. Correction is required.
When amending the claims, applicant is advised to carefully review all examined claims and make the necessary changes to ensure proper antecedent basis and dependency.
Claim Rejections - 35 USC § 112(a) or First Paragraph (pre-AIA )
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.
Claims 20-23 are 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
As stated in MPEP 2111.01, during examination, the claims must be interpreted as broadly as their terms reasonably allow. Claims 20-23 are directed in part to a method that requires contacting a genus of mogrosides having any structure with the protein of SEQ ID NO: 38, or a genus of variants of the polypeptide of SEQ ID NO: 38 having at least 90% sequence identity to the polypeptide of SEQ ID NO: 38, wherein said contacting is performed in host cells that have been modified by any means to synthesize mogrol or a genus of mogrosides, wherein said host cells express the protein of SEQ ID NO: 38, or the genus of variants of the polypeptide of SEQ ID NO: 38 having at least 90% sequence identity to the polypeptide of SEQ ID NO: 38. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation.
In University of California v. Eli Lilly & Co., 43 USPQ2d 1938, the Court of Appeals for the Federal Circuit has held that “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials”. As indicated in MPEP § 2163, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show that Applicant was in possession of the claimed genus. In addition, MPEP § 2163 states that a representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
There is a significant amount of structural variability with respect to the members of the genus of uridine diphospho-glucosyl transferases (UGT) required by the claims. In addition, there is no limitation with regard to the modifications that can be made to any host cell to produce any mogroside, mogrol or any mogroside precursor. While the specification in the instant application discloses the structure of the polypeptide of SEQ ID NO: 38 as well as the conversion of mogroside V to mogroside VI, and discloses a limited number of enzymes that when expressed in a host cell can produce a mogroside and/or a mogroside precursor, it provides no clue as to the structural elements required in (i) any polypeptide that when expressed in any host cell can allow the synthesis of any mogroside, mogrol or any mogroside precursor, and (ii) variants of the polypeptide of SEQ ID NO: 38 having the recited % sequence identity which have UGT activity and the corresponding mogroside substrate. No disclosure of a structure/function correlation has been provided which would allow one of skill in the art to recognize (i) which proteins can be used in any host cell to produce any mogroside, mogrol or mogroside precursor, and (ii) which variants of the polypeptide of SEQ ID NO: 38 having the recited % sequence identity have UGT activity and can use any mogroside or mogrol as a substrate.
The claims encompass a large genus of proteins which are structurally/functionally unrelated or substantially unrelated in structure. A polypeptide having 90% sequence identity with the polypeptide of SEQ ID NO: 38 allows for any combination of 46 amino acid modifications within SEQ ID NO: 38 (46 = 0.1x452; SEQ ID NO: 38 has 452 amino acids). The total number of variants of a polypeptide having a specific number of amino acid substitutions can be calculated from the formula N!x19A/(N-A)!/A!, where N is the length in amino acids of the reference polypeptide and A is the number of allowed substitutions. Thus, the total number of variants having 90% sequence identity to the polypeptide of SEQ ID NO: 38 that result from amino acid substitutions is 452!x1946/(452-46)!/46! or 1.54x10122 variants. A sufficient written description of a genus of polypeptides may be achieved by a recitation of a representative number of polypeptides defined by their amino acid sequence or a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. However, in the instant case, there is either no recited structural feature which is representative of all the members of the genus of proteins required by the host cells to produce mogrol or any mogroside, and the recited feature recited with regard to the variants of the polypeptide of SEQ ID NO: 38, is not representative of all the members of the genus. Furthermore, while one could argue that the few species disclosed are representative of the structure of all the members of the genus, it is noted that the art teaches several examples of how even highly structurally homologous polypeptides can have different enzymatic activities. For example, Witkowski et al. (Biochemistry 38:11643-11650, 1999; cited in the IDS) teach that one conservative amino acid substitution transforms a β-ketoacyl synthase into a malonyl decarboxylase and completely eliminates β-ketoacyl synthase activity. Tang et al. (Phil Trans R Soc B 368:20120318, 1-10, 2013; cited in the IDS) teach that two Dehalobacter reductive dehalogenases, CfrA and DcrA, having 95.2% sequence identity to teach other have exclusively different substrate (Abstract; page 7, left column, Discussion, CfrA and DcrA). Seffernick et al. (J. Bacteriol. 183(8):2405-2410, 2001; cited in the IDS) teach that two naturally occurring Pseudomonas enzymes having 98% amino acid sequence identity catalyze two different reactions: deamination and dehalogenation, therefore having different function. Therefore, since minor structural differences may result in changes affecting function, and no additional information correlating structure with the desired functional characteristics has been provided, one cannot reasonably conclude that the few species disclosed are representative of the structure of all the UGTs required by the claims and the enzymes required for any host cell to produce any mogroside, mogrol or mogroside precursor.
Due to the fact that the specification only discloses a limited number of species of the genus of enzymes required to synthesize a mogroside or a mogroside precursor, the protein of SEQ ID NO: 38, a single mogroside substrate for the protein of SEQ ID NO: 38, and the lack of description of any additional species by any relevant, identifying characteristics or properties, one of skill in the art would not recognize from the disclosure that Applicant was in possession of the claimed invention.
Claims 20-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for the production of a mogroside, wherein said method comprises contacting in vitro mogroside V with the protein of SEQ ID NO: 38 to produce mogroside VI, does not reasonably provide enablement for (a) a method to produce any mogroside by contacting in vivo or in vitro of any mogroside with a variant of the polypeptide of SEQ ID NO: 38 having at least 90% sequence identity to the polypeptide of SEQ ID NO: 38, (b) a host cell that has been genetically modified by any means to produce any mogrol or any mogroside, wherein said host cell expresses the protein of SEQ ID NO: 38 or any variant of the polypeptide of SEQ ID NO: 38 having at least 90% sequence identity to the polypeptide of SEQ ID NO: 38, or (c) a method to produce any mogroside wherein said method comprises contacting in vivo a mogrol or any mogroside synthesized by the host cell of (b). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 737, 8 USPQ2nd 1400 (Fed. Cir. 1988)) as follows: 1) quantity of experimentation necessary, 2) the amount of direction or guidance presented, 3) the presence and absence of working examples, 4) the nature of the invention, 5) the state of prior art, 6) the relative skill of those in the art, 7) the predictability or unpredictability of the art, and 8) the breadth of the claims. The factors which have led the Examiner to conclude that the specification fails to teach how to make and/or use the claimed invention without undue experimentation, are addressed in detail below.
The breadth of the claims. Claims 20-23 broadly encompass a method to produce any mogroside wherein said method comprises contacting a mogrol or any mogroside with a protein that expresses a polypeptide that comprises SEQ ID NO: 38 or a variant of the polypeptide of SEQ ID NO: 38 having at least 90% sequence identity to the polypeptide of SEQ ID NO: 38, wherein said contacting is performed in a host cell that has been genetically modified by any means to produce any mogrol or any mogroside, and wherein said host cell expresses the protein of SEQ ID NO: 38 or any variant of the polypeptide of SEQ ID NO: 38 having at least 90% sequence identity to the polypeptide of SEQ ID NO: 38. See Claim Rejections - 35 USC § 112(b) or Second Paragraph (pre-AIA ) for claim interpretation.
The enablement provided is not commensurate in scope with the claims due to the lack of information regarding the structural elements within the polypeptide of SEQ ID NO: 38 which are required and those which can be modified to obtain the required UGTs, the mogrosides that can be used as substrates of the recited UGTs, and the extremely large number of modifications that can be made to any host cell so that it can produce any mogroside, mogrol or mogroside precursors. In the instant case, the specification enables a method for the production of a mogroside, wherein said method comprises contacting in vitro mogroside V with the protein of SEQ ID NO: 38 to produce mogroside VI.
The amount of direction or guidance presented and the existence of working examples. The specification discloses the amino acid sequence of the polypeptide of SEQ ID NO: 38 as a UGT that can use mogroside V to produce mogroside VI as a working example. The specification also discloses a limited number of enzyme combinations that when expressed in a host cell can lead to such host cell to produce mogrosides and mogroside precursors. However, the specification fails to provide any clue as to the structural elements required in any protein that have UGT activity that can use any mogroside to produce another mogroside, the structural features within the polypeptide of SEQ ID NO: 38 required in a variant having the recited % sequence identity such that the variant has the same UGT activity as that of the polypeptide of SEQ ID NO: 38, and the modifications can be made to any host cell to produce mogrosides or mogroside precursors.
The state of prior art, the relative skill of those in the art, and the predictability or unpredictability of the art. The amino acid sequence of a polypeptide determines its structural and functional properties. While the art discloses a limited number of enzymes associated with the synthesis of mogrosides and mogroside precursors, and a limited number of UGTs, neither the specification nor the art provide a correlation between structure and function such that one of skill in the art can envision the structure of any protein that when expressed in any host cell, it can catalyze the formation of any mogroside or mogroside precursor, or the structure of any UGT that can have the same UGT activity as that of the polypeptide of SEQ ID NO: 38. In addition, the art does not provide any teaching or guidance as to which modifications can be made to any host cell to produce any mogroside or mogroside precursor.
While the argument can be made that the structure/identity of those enzymes and their corresponding genes can be obtained by structural homology, the art clearly teaches that (i) there is a high level of unpredictability associated with accurate functional annotation of proteins based solely on structural homology, and (ii) modification of a protein’s amino acid sequence to obtain the desired activity without any guidance/knowledge as to which amino acids in a protein are tolerant of modification and which ones are conserved is highly unpredictable. For example, Singh et al. (Current Protein and Peptide Science 19(1):5-15, 2018; cited in the IDS) disclose different protein engineering approaches and state that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility and conformational changes (page 11, left column, last paragraph). Sadowski et al. (Current Opinion in Structural Biology 19:357-362, 2009; cited in the IDS) teach that much of the problem in assigning function from structure comes from functional convergence, where although a stable structure is required to perform many functions, it is not always necessary to adopt a particular structure to carry out a particular function (page 357, right column, first full paragraph). Sadowski et al. further explain that the unexpected and significant difficulties of predicting function from structure show that the potential of structural models for providing novel functional annotations has not yet fully realized. Sadowski et al. also states that while a few successes have been achieved which required manual intervention, the ability to vary the requirements for specificity in prediction means that it is difficult to determine how useful the end result may be for the user (page 361, left column, first full paragraph). The teachings of Singh et al. and Sadowski et al. are further supported by the teachings of Witkowski et al., Tang et al. and Seffernick et al. already discussed above, where it is shown that even small amino acid changes result in unpredictable enzymatic activity changes.
The quantity of experimentation required to practice the claimed invention based on the teachings of the specification. While methods of generating or isolating variants of a polypeptide and enzymatic assays were known in the art at the time of the invention, it was not routine in the art to screen by a trial and error process for an essentially infinite number of proteins to find a protein with the desired activity. Similarly, it was not routine in the art to test an infinite number of modifications, such as disruption of genes of unknown function, or the expression of transcription inducers or repressors, to find those that would result in the production of any mogroside or mogroside precursor. In the absence of (i) a rational and predictable scheme for selecting those proteins most likely to have the desired functional features, (ii) a rational and predictable scheme for selecting those modifications that can be made to any host cell to produce mogrosides or mogroside precursors, and/or (iii) a correlation between structure and the desired activity, one of skill in the art would have to test an essentially infinite number of proteins and modifications to determine which ones would provide the desired functional effect.
Therefore, taking into consideration the extremely broad scope of the claim, the lack of guidance, the amount of information provided, the lack of knowledge about a correlation between structure and the desired function, and the high degree of unpredictability of the prior art in regard to structural changes and their effect on function, one of ordinary skill in the art would have to go through the burden of undue experimentation in order to practice the claimed invention. Thus, Applicant has not provided sufficient guidance to enable one of ordinary skill in the art to make and use the invention in a manner reasonably correlated with the scope of the claims.
Conclusion
No claim is in condition for allowance.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to DELIA M RAMIREZ, Ph.D., whose telephone number is (571) 272-0938. The examiner can normally be reached on Monday-Friday from 8:30 AM to 5:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert B. Mondesi, can be reached at (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
/DELIA M RAMIREZ/Primary Examiner, Art Unit 1652
DR
September 2, 2026
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