DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This Office action is in response to the communications filed 4-9-26 and 5-12-26.
Claims 17, 19-31 are pending in the instant application.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 5-12-26 has been entered.
Response to Arguments and Amendments
Withdrawn Objections/Rejections
Any objections or rejections not repeated in this Office action are hereby withdrawn.
Maintained Rejections
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 17, 19-23, 28, 29 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claims are drawn to compositions comprising miR-3184 and optionally further comprising let-7b, let-7c, miR-19b, miR-22, miR-24, miR-25, miR-29a, miR-30a, miR-92a, miR-99a, miR-100, miR-197, miR-30d, miR-181a, miR-181b, miR-205, miR-210, miR-221, miR-125b, miR-125a, miR-149, miR-193a, miR-320a, miR-200a, miR-99b, miR-130b, miR-30e, miR-375, miR-378a, miR-151a, miR-425, miR-484, miR-146b, miR-574, miR-652, miR-320c, miR-3141, let-7d, miR-196a, miR-187, miR-516a, miR-92b, and miR-3126, let-7d, miR-196a, miR-187, miR-516a, miR-92b, miR-3126, miR-3141 and/or miR-3126.
Claims 17, 19-23, 28, 29 are rejected because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because the claimed invention is directed to products of nature without significantly more. The claim(s) recite(s) products of nature including various microRNA molecules (a.k.a. mir molecules).
This judicial exception is not integrated into a practical application because they recite products of nature. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because they recite compositions comprising products of nature. He claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because the claimed invention is directed to non-statutory subject matter. The claimed invention is directed to products of nature comprising compositions of mir molecules. These molecules are naturally occurring.
What’s more, the claims do not include any elements that add significantly more to any judicial exceptions, and do not include features that demonstrate that the recited products are markedly different from what exists in nature. The molecules perform in their natural way, serve the ends nature originally provided, and act quite independently of any effort of patentee. There are no marked differences in the function or structure of these naturally occurring molecules, and their characteristics do not change from that occurring in nature.
In sum when the relevant factors are analyzed, they weigh toward ineligibility under 35 U.S.C. 101. Therefore, the claims are non-statutory, and the rejection under 35 U.S.C. 101 is appropriate.
Applicant’s Arguments
Applicant's arguments filed 4-9-26 have been fully considered but they are not persuasive. Applicant argues the following:
It is well understood in the art that "breast milk fortifiers" and "infant milk fortifiers" are specialized nutritional supplements and do not refer to products of nature. In particular, "to fortify" is understood, in the context of nutrition, as "to enrich (food) by adding ingredients (such as vitamins or minerals) to improve the nutritional value."2 Additionally, an "infant formula" is well understood to refer to a nutritional composition intended for infants during the first year of life. Such compositions are understood to satisfy the nutritional requirements for the infant by including necessary proteins, lipids, carbohydrates and other nutrients. Claim 17 further recites that the nutritional composition is not natural human or animal milk. Accordingly, an infant formula is not a naturally occurring product.
Moreover, the specification defines "nutritional composition" as "a composition which nourishes a subject" and "does not include natural milk of human or animal origin." Thus, these terms also exclude natural milk. Accordingly, the recited nutritional composition in a form selected from the group consisting of an infant formula, a breast milk fortifier, and an infant formula fortifier is not a product of nature.
Response to Applicant’s Arguments
Contrary to Applicant’s assertions, the claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the nucleic acids or miR molecules claimed have little or no difference from naturally occurring products. The claims, including compositions containing infant formula and fortifiers, do not include any elements that add significantly more to any judicial exceptions, and does not include features that demonstrate that the recited products are markedly different from what exists in nature (e.g, there are no covalent or other modifications to the miR molecules). Therefore, the claims of miR molecules amount to nothing more than obvious derivatives of natural occurring products and steps intending to utilize them.
The claimed invention is directed to compositions in combinations with naturally occurring nucleic acid molecules, whether isolated or not, that are not patent eligible pursuant to the Supreme Court decision in Association for Molecular Pathology v. Myriad Genetics, Inc. (6-13-13).
For these reasons, the instant rejection is properly maintained.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 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 24-27, 30 and 31 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for an in vitro Caco2 cell model for evaluating the effect of miR-3184-3p, miR-3126-5p, and miR-3141 on gene expression, does not reasonably enable methods of promoting healthy growth and development and preventing any metabolic disorders later in life in any subject comprising administering a nutritional composition comprising miR-3184, or methods to modulate gene expression of one or more genes selected from Lipin 2 and Insulin Like Growth Factor 2 using miR-3184. 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 for the reasons of record set forth in the Office action mailed 1-14-26, and as set forth below.
Applicant’s Arguments
Applicant's arguments filed 4-9-26 have been fully considered but they are not persuasive. Applicant argues the following:
The experimental data in the specification demonstrates enablement for the claimed methods of promoting healthy growth and development, preventing metabolic disorders later in life, and evaluating the effect of the recited miRNAs on gene expression of the recited genes.
In this regard, the enablement requirement may be met by animal tests or in vitro data, and an in vitro model example constitutes a working example if that example correlates with a disclosed or claimed method.5 Applicant notes that "a rigorous or an invariable exact correlation is not required."6 The Examples of the present disclosure include data from a Caco2 in vitro cell model to evaluate the effect of miR-3184 on gene expression.7 As can be seen in Table 4, miR- 3184 significantly affected the expression of Lipin 2 and IGF2. Therefore, the cell model disclosed in the present specification provides enablement for the method to modulate gene expression of one or more genes selected from: Lipin 2 or Insulin Like Growth Factor 2.
Moreover, the inventor explained in the Declaration how one of ordinary skill in the art would conclude that miRNAs, especially milk-derived miRNAs, are stable during digestion and are capable of being absorbed in the human gastrointestinal tract where they may exert local and systemic biological effect.8 For example, in vitro digestion experiments in the literature show that milk-derived miRNAs remain intact after simulated oral, gastric, and intestinal digestion, demonstrating their ability to survive passage through the gastrointestinal tract.
Additionally, the Declaration explains how the skilled artisan would readily understand and accept that promoting postnatal gene expression of IGF2 and Lipin-2 supports healthy growth and development and reduces the likelihood of metabolic disorders later in life.10 For instance, IGF2 is known to be essential for normal fetal and postnatal growth whereas impaired IGF signaling leads to impaired growth."1 Also, Lipin-2 is known to suppress chronic inflammatory signaling linked to metabolic disease.12 Thus, the promotion of Lipin-2 expression contributes to long-term metabolic stability and disease prevention.13
Accordingly, because the inventors surprisingly found that miR-3184 significantly increases the expression of both IGF2 and Lipin-2, the skilled artisan would expect and understand that administration of a nutritional composition comprising miR-3184 would lead to the promotion of healthy growth and development in a subject and the prevention of metabolic disorders later in life.
The Patent Office has not provided any evidence that the model disclosed in the present specification does not correlate with the claimed methods. Therefore, the examples disclosed in the specification provide enablement for the present claims.
Response to Applicant’s Arguments
Applicant's arguments filed 4-9-26 have been fully considered but they are not persuasive. Applicant has provided publications showing the stability of miR molecules upon oral administration. Despite this, and contrary to Applicant’s arguments and assertions, the long term effects of administering miR 3184 (and/or miR-3184-3p and/or miR-3184-5p) to a subject cannot be determined from the in vitro transfection of Caco2 cells using the DharmaFect transfection reagent from Dharmacon, and incubating the cells for 48-72 hours. In vivo results cannot be extrapolated from the in vitro transfection of a single cell line using commercial transfection reagents. The biological roles or miR-3184 are complex and are still being investigated. The state of the art regarding miR-3184, its targets, and its role on growth and development in animals and/or humans has not been fully determined. See, e.g., Xu et al (Cancer Science, Vol. 113, No. 8, pages 2668-2680 (2021)), describing the enrichment of miR-3184 in cerebrospinal fluid exosomes in glioma patients. MiR-3184 was found to significantly promote glioma progression and invasion.
The Breadth of the Claims:
The claims are drawn to methods of promoting healthy growth and development and preventing any metabolic disorders later in life in any subject comprising administering a nutritional composition comprising miR-3184, and methods to modulate gene expression of one or more genes selected from Lipin 2 and Insulin Like Growth Factor 2 using miR-3184 in a subject.
The Teachings in the Specification:
As stated previously, the specification teaches the following:
Eleven dynamic miRNAs were identified with either an increasing or a decreasing expression during lactation. These are shown in Tables 1 and 2 below. Thirty-eight miRNAs were identified which were highly and stably expressed during lactation. These are shown in Table 3…
Cell culture and transfection Caco2 were cultured in DMEM (+) L-glutamate (-) Pyruvate supplemented with 1X non-essential amino acids, 1mM Sodium Pyruvate and 20 % FBS. Cells were split three times a week without exciding 80% confluency. For transfection, cells were plated in 24 well plate (50,000 cells / well) to obtain a 50% confluency the day after. Transfection was performed using DharmaFect reagent from Dharmacon… following manufacturer recommendation. Briefly, 1.25 ul / well of DharmaFect 4 and a final concentration of 25 nM of miRNA were used. For each time point (i.e. 48h and 72h post transfection) media was removed and cells were washed with 1 ml of cold PBS without calcium chloride and magnesium chloride. Cells were frozen directly on plate after aspirating cold PBS. miRNA were purchased from Dharmacon…, see P 33.
An in vitro Caco2 cell model was used to evaluate the effect of miR-3184-3p, miR-3126-5p, and miR-3141 on gene expression. miR-3184-3p, miR-3126-5p, and miR-3141 significantly affected the expression of the genes shown in Table 4…
[Citations omitted] [Emphases added].
Contrary to Applicant’s assertions, the examples provided in the instant specification, of an in vitro Caco2 cell model for evaluating the effect of miR-3184-3p, miR-3126-5p, and miR-3141 on gene expression, are not representative or correlative of the ability to provide methods of promoting healthy growth and development and preventing any metabolic disorders later in life in any subject comprising administering a nutritional composition comprising miR-3184, or to provide methods to modulate gene expression of one or more genes selected from Lipin 2 and Insulin Like Growth Factor 2 using miR-3184 in any subject. There is no teaching in the specification as to the ability to provide in vivo effects as instantly claimed.
In light of the teachings in the art and the specification, one skilled in the art would not accept on its face the examples provided in the instant disclosure, and summarized above, as being correlative or representative of the ability to provide therapeutic effects in any subject as instantly claimed.
Since the specification fails to provide the requisite guidance for delivery and provision of therapeutic effects in a subject, and since determination of the factors required for accomplishing therapeutic efficacy in a subject is highly unpredictable, it would require undue experimentation to practice the invention over the broad scope claimed.
For the aforementioned reasons, the instant rejection under 35 U.S.C. 112, first paragraph is properly maintained.
Conclusion
Certain papers related to this application may be submitted to Art Unit 1637 by facsimile transmission. The faxing of such papers must conform with the notices published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 C.F.R. ' 1.6(d)). The official fax telephone number for the Group is 571-273-8300. NOTE: If Applicant does submit a paper by fax, the original signed copy should be retained by applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jane Zara whose telephone number is (571) 272-0765. The examiner’s office hours are generally Monday-Friday, 10:30am - 7pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jennifer Dunston, can be reached on (571)-272-2916. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (703) 308-0196.
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Jane Zara
6-25-26
/JANE J ZARA/Primary Examiner, Art Unit 1637
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