DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .2. This action is in response to the amendment filed on 23 December 2025. Applicant's arguments and amendments to the claims have been fully considered but do not place the application in condition for allowance. All rejections and objections not reiterated herein are hereby withdrawn.
Election/Restrictions
3. In the reply of 26 August 2025, Applicant elected without traverse Group II and the species of miR-425-5p. With respect to the elected species, in the reply filed on 23 December 2025, the claims were amended to require measuring the expression of both miR-425-5p and miR-145-5p. Accordingly, the elected species is now considered to be the combination of miR-425-5p and miR-145-5p.
Claim Status
4. Claims 1-7 and 9-11 are pending.
Claims 1-6 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 7 and 9-11 read on the elected invention and have been examined herein.
Maintained / Modified Claim Rejections - 35 USC § 101
5. 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 7 and 9-11 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a law of nature / natural phenomenon, and/or an abstract idea without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Applicant' s attention is directed to MPEP 2106 “Patent Subject Matter Eligibility” which discusses the Alice/Mayo two-part test for evaluating subject matter eligibility.
Regarding Step 1 of the subject matter eligibility test set forth at MPEP 2106III, the claims are directed to the statutory category of a process.
Regarding Step 2A, prong one, the claims recite the judicial exception of a law of nature. The claims recite the correlation between the level of gene expression of miR-425-5p or miR-145-5p and ovarian reserve, high activation of ovarian function or low risk of early ovarian failure. Note that the claims are directed to a method for detecting “a marker to provide information for diagnosing age-related decline in ovarian reserve.” Additionally, the claims recite “determining that the subject has high ovarian reserve or high activation of ovarian function, when the measured expression level of the miR-145-5p is decreased compared to the measured expression level in the normal control group; or when the measured expression level of the miR-425-5p is increased compared to the measured expression level in the normal control group, or determining that the subject has a low risk of early ovarian failure, when the measured expression level of the miR-145-5p is decreased compared to the measured expression level in the normal control group.” As in Mayo Collaborative Services v. Prometheus, the recited relationship is a natural phenomenon that exists apart from any human action. See also Cleveland Clinic Foundation v. True Health Diagnostic, LLC, 2018-1218 (Fed Cir. 2019) which states that “The re-phrasing of the claims does not make them less directed to a natural law.”
The claims also recite the judicial exception of an abstract idea and particularly mental processes.
MPEP 2106.04(a) states that the enumerated groupings of abstract ideas include:
“1) Mathematical concepts – mathematical relationships, mathematical formulas or equations, mathematical calculations (see MPEP § 2106.04(a)(2), subsection I);…
3) Mental processes – concepts performed in the human mind (including an observation, evaluation, judgment, opinion) (see MPEP § 2106.04(a)(2), subsection III).”
Herein, the claims require performing a step of "comparing" the expression level of miR-425-5p in a subject to the level of a gene of a control group. Neither the specification nor the claims set forth a limiting definition for "comparing" and the claims do not set forth how comparing is accomplished. The broadest reasonable interpretation of the “comparing” step is that this step may be accomplished by critical thinking processes. Such “comparing” thereby encompasses only an abstract idea / process.
The claims require performing the step of “determining” that the subject has high ovarian reserve or high activation of ovarian function or a low risk of early ovarian failure. Neither the specification nor the claims set forth a limiting definition for "determining" and the claims do not set forth how “determining” is accomplished. The broadest reasonable interpretation of the “determining” step is that this step may be accomplished by critical thinking processes such that an individual mentally makes a determination based on the compared expression levels. Such “determining” thereby encompasses processes that may be performed mentally and thus is an abstract idea.
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). The additionally recited steps of measuring the expression level of the miRNAs is part of the data gathering process necessary to observe the judicial exception. This step does do not practically apply the judicial exception.
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps - either in isolation or combination, amount to significantly more than the judicial exception.
Herein, the claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than routine and conventional activity and do not add something “significantly more” so as to render the claims patent-eligible. The additionally recited step of measuring the miRNA biomarkers, including by contacting a sample with a nucleic acid complementary to the biomarker or by performing a real- time PCR or RT-PCR analysis, was well-known, routine and conventional in the prior art. This finding is evidenced by the teachings in the specification which teach that known kits and devices were used to measure miR-425-5p and miR-145-5p levels (e.g., para [0076]; note that paragraph numbering herein is with respect to the published application).
Further, this finding is evidenced by the teachings in the prior art. For example, Xu et al (Endocrinology. 2011. 152(10:: 3941-3951; cited in the IDS), Kim et al (Geburtsh Frauenhelk. 2016. 76: 704-708; cited in the IDS) and Roth et al (J Assist Reprod Genet. 2014. 31: 355-362; cited in the IDS) each teach detecting miRNA levels in samples from a subject using real-time qRT-PCR (e.g., p. 3942, col. 2 to p. 3943, col. 1 of Xu et al, and p. 705, col. 2 of Kim et al; and p. 356, col. 2 to p. 357, col. 1 of Roth et al). See also Tewari, M. (U.S. 20110160290) and Chen et al (Oncotarget. 2018. 9(29): 20451-20466) which each teach methods of measuring miRNA expression levels by performing RT-PCR, as discussed in detail below.
See also MPEP 2106.05(d) II which states that:
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
vii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
Note that while the claims recite detecting the expression of the particular biomarker of miR-425-5p, the identity of the biomarker is part of the judicial exception and not something in addition to the recited judicial exceptions. The claims do not require using a particular non-conventional reagent, such as a particular, non-conventional probe or primer consisting of or comprising a specific nucleotide sequence so as to add something ‘significantly more’ to the recited judicial exceptions.
In Mayo v. Prometheus, the Supreme Court stated: "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately."
This is similar to the present situation wherein the additional steps and elements are recited at a high degree of generality and are all routine, well understood and conventional in the prior art. The recited steps and elements do not provide the inventive concept necessary to render the claims patent eligible. See also Genetic Technologies Ltd. v. Merial L.L.C. 818 F.3d at 1377, 1379 (Fed. Cir. 2016).
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.Response to Remarks:
The response states that “the method recited in independent claim 7 is a method of performing manipulations and operations using a physical entity, specifically performing manipulations of a sample collected from a subject to measure the expression level of miR- 145-5p and miR-425-5p in the sample.” Applicant asserts that the claim as a whole is not directed to an abstract idea. It is argued that “the combination of steps (i) and (ii) demonstrate that the claim, as a whole, is not directed to an abstract idea, and, if it recites an abstract ideal at all, integrates that abstract idea into the above-explained practical application, which allows the expression level of miR-145-5p and miR-425-5p to indicate whether a female subject has high/low ovarian reserve or high/low activation of ovarian function.”
These arguments have been fully considered but are not persuasive. First it is noted that the rejection does not state that the claim as a whole is directed to an abstract idea. Secondly, the claims have been examined herein using the Alice/Mayo two-part test for evaluating subject matter eligibility outlined in MPEP 2106. MPEP 2106.05(c) states “It is noted that while the transformation of an article is an important clue, it is not a stand-alone test for eligibility.” It goes on to state “if a claim fails the Alice/Mayo test (i.e., is directed to an exception at Step 2A and does not amount to significantly more than the exception in Step 2B), then the claim is ineligible even if it passes the M-or-T test” (Emphasis added). Herein, the claims fail the Alice/Mayo test for the reasons discussed in detail above and thereby the presence of a transformative - i.e., measuring - step in the claim does not render the claim patent-eligible.
Thirdly, the claims do not in fact integrate the abstract idea into a practical application. While the expression level of miR-145-5p and miR-425-5p are asserted to be indicative of whether a female subject has high/low ovarian reserve or high/low activation of ovarian function, this the judicial exception of the law of nature - i.e., the naturally occurring relationship between the level of the miRNAs and ovarian reserve. This is not a practical application of the judicial exception. See MPEP § 2106.04(d) for more information regarding the evaluation of whether a claim reciting a judicial exception is integrated into a practical application.
New Claim Rejections - 35 USC § 112 - New Matter
6. 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 7 and 9-11 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 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. This is a new matter rejection.
The disclosure as originally filed does not provide support for the amendment to claims 7 and 9-11 to recite that the method is one for diagnosing “age-related decline” in ovarian reserve.
The response states “(t)he ‘diagnosing age-related decline in ovarian reserve’ is supported by the use of naturally aged models in paragraph [0064] and the diagnosis of early ovarian failure in paragraph [0086], for example.”
However, para [0064] (with respect to the published application) does not disclose measuring the level of miR-145-5p and miR-425-5p as diagnostic of age-related decline in ovarian reserve. Rather, para [0064] states:
“As shown in FIG. 1 , 5×105 human placenta-derived mesenchymal stem cells were injected through the tail vein of naturally aged 52-week-old female mice three times at 10-day intervals, and groups at week 1, week 2, week 3, and week 5 were defined as stem cell treatment experimental groups (hereinafter referred to as “experimental groups”), and a group to which the same amount of PBS was injected under the same conditions was defined as a control group, and the groups were analyzed for comparison.”
Thus, para [0064] discloses injecting human placenta-derived mesenchymal stem cells into 52-week old mice at 10 week intervals.
Para [0086] states:
“Therefore, changes in the expression of miR-145-5p and miR-425-5p present in the blood may be used as a marker of follicle development to predict ovarian reserve of women. In addition, changes in the expression of miR-145-5p and miR-425-5p present in the blood may predict ovarian function, such as hormone production, and be used as a marker for diagnosis of early ovarian failure.”
However, early ovarian failure is not caused by age - i.e., the ovarian failure occurs early and thereby is not an “age-related decline” in ovarian reserve. It is unclear as to how the cited portions of the specification are being relied upon to establish that the disclosure as originally filed provides basis for the amendment to recite “age-related decline in ovarian reserve” in place of “ovarian reserve.”
If Applicant maintains that the originally filed disclosure provides basis for the amended claims, Applicant should point to specific teachings (e.g., by paragraph number) in the present application to establish basis for each of the recitations set forth in the claims and explain how the cited teachings do provide such basis. Herein, there is no literal basis for the amendment in the specification and Applicant’s comments do not clarify why the cited paragraphs (i.e., [0064] and [0086]) are intended to provide basis for the amendment.
See MPEP 2163 II at “(b) New Claims, Amended Claims, or Claims Asserting Entitlement to the Benefit of an Earlier Priority Date or Filing Date under 35 U.S.C. 119, 120, 365, or 386” which states:
“To comply with the written description requirement of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, or to be entitled to an earlier priority date or filing date under 35 U.S.C. 119, 120, 365, or 386, each claim limitation must be expressly, implicitly, or inherently supported in the originally filed disclosure.”
Maintained Claim Rejections - 35 USC § 112 - Enablement
7. Claims 7 and 9-11 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 methods comprising measuring the level of miR-425-5p and miR-145-5p in a biological sample obtained from a subject,
does not reasonably provide enablement for methods for diagnosing age-related ovarian reserve in a subject, comprising: measuring an expression level of miR-425- 5p and miR-145-5p in a subject suspected of having ovarian hypofunction; and comparing the measured expression level with an expression level of a gene of a normal control group, and determining that the subject has high ovarian reserve or high activation of ovarian function, when the measured expression level of the miR-145-5p is decreased compared to the measured expression level in the normal control group; or when the measured expression level of the miR-425-5p is increased compared to the measured expression level in the normal control group, or determining that the subject has a low risk of early ovarian failure, when the measured expression level of the miR-145-5p is decreased compared to the measured expression level in the normal control group, or when the measured expression level of the miR-425-5p is increased compared to the measured expression level in the normal control group. 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 use the invention commensurate in scope with these claims.
The following factors have been considered in formulating this rejection (In re Wands, 858F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988): the breadth of the claims, the nature of the invention, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art, the amount of direction or guidance presented, the presence or absence of working examples of the invention and the quantity of experimentation necessary.
The claims are drawn to a method of detecting a marker to provide information for diagnosing ovarian reserve, comprising: measuring an expression level of miR-425- 5p in a subject suspected of having ovarian hypofunction; and comparing the measured expression level with an expression level of a gene of a normal control group. Breadth of the claims:
The breadth of the claims is considered to be significantly broad. The claims encompass methods in which miR-425-5p and miR-145-5p levels are measured in a sample obtained from the subject, wherein such samples may be any samples including a blood sample, urine, feces, saliva, and any tissue sample.
The claims also encompass methods wherein the subject is any subject, including subjects that are human, a dog, a cat, a mouse, a rat, a rabbit, a horse, sheep, a cow, a goat, or a pig (claim 9). See also para [0012] which states:
“The miRNA may be isolated from a biological sample isolated from a subject suspected of ovarian hypofunction or a subject suspected of having low ovarian reserve. The subject may be a mammal, and may be a human, a dog, a cat, a rat, a mouse, a hamster, a rabbit, a horse, sheep, a cow, a goat or a pig. The subject may be of a female phenotype.”
The claims also encompass diagnosing / determining a number of phenotypes of the subject based on the expression level of miR-425p or miR-145-5p, including activation of primordial follicles, production of ovarian hormones, or ovarian hypofunction, high activation of ovarian function and low risk of ovarian failure. For example, the specification states:
“[0027] The term “ovarian reserve” refers to a marker indicating a number of oocytes in the ovary that may be ovulated, and quality of the oocytes obtained by induction of ovulation. The ovarian reserve may refer to an index indicating fertility, ovarian function, or early menopause.
[0028] In an example, the ovarian reserve may indicate whether or not there is activation of primordial follicles, production of ovarian hormones, or ovarian hypofunction…
[0031] The term “low ovarian reserve” may mean that a number of oocytes in the ovaries is small and the quality of the oocytes is relatively low. Therefore, low ovarian reserve may mean low fertility, a high risk of premature menopause, or a high risk of diseases related to ovarian hypofunction. In addition, low ovarian reserve may also mean a decrease in ovarian function.
[0032] “High ovarian reserve” may mean that a number of oocytes in the ovaries is large and the quality of the oocytes is relatively high. Thus, high ovarian reserve may mean high fertility, a low risk of early menopause or a low risk of diseases related to ovarian hypofunction. In addition, high ovarian reserve may also mean an increase in ovarian function.” Emphasis added.
Teachings in the specification: The specification teaches injecting human placenta-derived mesenchymal stem cells into aged mice (Example 1). It is reported that the number of primary follicles more than doubled after 2 and 3 weeks after repeated injections of the human placenta-derived mesenchymal stem cells (para [0071]). It is reported that the hormones AMH and E2 (estradiol) increased in the mice. The specification (para [0073]) concludes that “when human placenta-derived mesenchymal stem cells settle in the aged ovary, the stem cells were confirmed to improve ovarian reserve by increasing development of early follicles, and a phenotype of enhanced ovarian function was observed through production of ovarian hormones.”
The specification teaches assaying serum samples from the mice and reports that miR-425-5p was overexpressed and miR-145-5p was decreased in the serum of mice injected with the human placenta-derived mesenchymal stem cells (para [0078]).
However, it is noted that Figure 4a appears to show that the level of change of miR-145-5p was not significant:
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It is also unclear as to why Figure 4b shows the level of miR-145-5p to be less in mice who have just received the hPD-MSC injection as compared to control mice injected with PBS at week 1, but higher than the control mice at week 5, particularly since Applicant is asserting that a decrease in miR-145-5p is indicative of improvement in ovarian reserve (as a result of the hPD-MSC treatment).
The specification (para [0083-0084]) further teaches that “miR-425-5p targets Grem2, a BMP antagonist, and as a result of confirming the change in protein expression in the ovaries, it was observed that protein expression was lower in the week-2 and week-3 groups after stem cell injection compared to the control group…The above results indicate that the expression of circulating miRNAs present in the blood is changed by human placenta-derived mesenchymal stem cells injected into aged mice, and the change in their expression stimulates the BMP signaling pathway in the ovary.”
It is also disclosed that “miR-145-5p was found to target genes belonging to the TGFβ superfamily (Acvr1b, Acvr2a, Bmpr2, Tgfbr2, Smad1, Smad3)” (para [0080]).
However, the specification has not established that the results obtained with aged mice injected with human placenta-derived mesenchymal stem cells can be extrapolated to a representative number of non-mouse subjects who are not injected with human placenta-derived mesenchymal stem cells. There is no clear showing that the level of miR-425-5p in any subject, including human subjects, or in any sample from a subject will be predictive of any phenotype characteristic of ovarian reserve, including the activation of primordial follicles, production of ovarian hormones, or ovarian hypofunction.
Unpredictability in the art:
There is a high level of unpredictability in the art in extrapolating the results obtained with a mouse injected with human placenta-derived mesenchymal stem cells, to any other animal to diagnose any attribute of a subject that is correlated with the claimed phenotypes associated with ovarian reserve.
For example, Tewari, M. (U.S. 20110160290) teaches that an increase in
the expression level of miR-425- 5p in plasma samples is correlated with the occurrence of ovarian cancer (e.g., para [0020]). Chen et al (Oncotarget. 2018. 9(29): 20451-20466) teaches that an increase in the expression level of miR-425-5p was detected in serous ovarian carcinoma (SOC) tissue samples from subjects having metastasis, as well as subjects having either chemotherapy sensitive or resistant/refractive SOC (Tables 2-4 and p. 20458 final para, and p. 20460, first para). The findings of Tewari and Chen seem to be in opposition with the hypothesis set forth in the present specification that an increase in the expression level of miR-425-5p is diagnostic of a high ovarian reserve, including the phenotypes / attributes of high activation of ovarian function, activation of primordial follicles and production of any ovarian hormone.
The unpredictability in the art is also supported by the teachings of Battaglia (Biology Reproduction. 2016. 95(6):131, p. 1-13; cited in the IDS) which reports that miR-425-5p and miR-145 expression levels in human oocytes varied significantly within the samples analyzed from both young and old oocytes (see “Results” at p. 4 and Table 1 “Unsteadily expressed”). That is, miR-425-5p was amongst the 91 miRNAs that 91 “showed high variability among the different samples within the same group (Table 1 and Fig. 1)” - see p. 6, col. 1. Battaglia identified miRNAs that were differentially expressed between old and young oocytes - i.e., miRNAs indicative of reproductive aging. However, Battaglia did not identify miR-425-5p or miR-145 as a miRNA whose expression level varied between old and young oocytes in humans.
The general unpredictability in the art of using miRNA expression profiles to predict a phenotype is supported by the teachings of Tumilson et al. (Molecular Neurobiology. 2014. 50: 545-558). Tumilson states that “Researchers believe that the lack of clinical miRNA biomarkers compared to the number identified in research is due to limitations in standardizing of sample type collection, determining optimal methods of extraction, and processing of both samples and data, all of which can affect the reproducibility of individual findings.”
Tian et al (PLOS One. 5 January 2012. 7(1): e29551) teaches that miRNA expression results obtained using microarray analysis are often not reproducible due to variations in miRNA quality (p.1, col. 2 and p. 4, col. 2).
Zhou et al (Scientific Reports. 10 June 2015. 6:11251) discusses the lack of reproducibility of miRNA profiling results between laboratories and states that the inconsistencies may be explained by differences in research methods, tested populations and sample diversity (see, e.g., p.2, second paragraph and p. 9, first full para).
Additionally, there is a high level of unpredictability in the art in extrapolating the miRNA expression results obtained in one sample type to other sample types. Modification of expression levels most frequently occurs in only a subset of cells that are directly involved in a phenotype. The levels of particular miRNAs and proteins are well known to vary significantly between different cell, tissue and fluid types. Given that expression is often cell-type or tissue-type specific and that changes in gene expression patterns associated with a disease, such as cancer, are often variable between the particular tissue types that are affected by the disease, the identity of particular biomarkers whose expression is increased or decreased is expected to be different for different cell, tissue and body fluid types.
The unpredictability in the art is supported by the teachings of Heggard et al (International Journal of Cancer. 04 May 2011. 102. 130: 1378-1386) wherein it is disclosed that expression levels of miRNAs in serum did not correlate well with levels in plasma (see abstract).
Additionally, Golub (PGPUB 20110015080) teaches that many miRNAs have tissue specific expression patterns. For example, miR-122a is expressed exclusively in the liver and miR-124a is a “brain-specific miRNA” (para [0211]).
Regarding the fact that the claims encompass diagnosing ovarian reserve in any organism, it is noted that the results provided in the specification are limited to mouse subjects injected with human placental mesenchymal stem cells. It is unpredictable as to whether the results obtained in the specification can be extrapolated to any other subject in the absence of any information regarding miR-425-5p expression levels in a representative number of subjects, and sample types from subjects, having normal ovary function and having high or low ovarian reserve.
Additionally, claim 11 recites that the measuring of the expression level of miR-425-5p and miR-145-5p is accomplished by performing protein assays, such as immunoblotting, enzyme-linked immunosorbent assay (ELISA), immunohistochemical staining, protein chip, immunoprecipitation. However, miR-425-5p and miR-145-5p are not expressed as a protein. No guidance is provided in the specification as to how to predictably detect the expression level of miR-425-5p and miR-145-5p by performing the recited protein detection assays.
Extensive experimentation would be required to perform the broadly recited methods. Such experimentation includes ascertaining if miR-425-5p is expressed at an increased or decreased level in a representative number of different sample types obtained from a representative number of diverse subjects and determining if this increase or decrease in miR-425-5p expression is correlated with a representative number of phenotypes associated with ovarian reserve, including the expression level of any ovarian hormone, the activation of ovarian function, the activation of primordial follicles, or ovarian hypofunction. The experimentation would also require developing in vivo methods in which the level of miR-425-5p can be measured directly in any subject and developing methods in which protein assays are used to detect miR-425-5p levels. Further experimentation would require performing the above experiments with miR-145-5p. The results of such experimentation are highly unpredictable and the experimentation is undue.
As set forth in Rasmusson v. SmithKline Beecham Co., 75 USPQ2d 1297, 1302 (CAFC 2005), enablement cannot be established unless one skilled in the art "would accept without question" an Applicant's statements regarding an invention, particularly in the absence of evidence regarding the effect of a claimed invention. Specifically:
"As we have explained, we have required a greater measure of proof, and for good reason. If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to "inventions" consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the "inventor" would be rewarded the spoils instead of the party who demonstrated that the method actually worked. That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis."
Moreover, case law has established that '(t)o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.'" In re Wright 990 F.2d 1557, 1561. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) it was determined that '(t)he scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art". The amount of guidance needed to enable the invention is related to the amount of knowledge in the art as well as the predictability in the art. Furthermore, the Court in Genetech Inc. v Novo Nordisk 42 USPQ2d 1001 held that '(I)t is the specification, not the knowledge of one skilled in the art that must supply the novel aspects of the invention in order to constitute adequate enablement".
In the present situation, in view of the unpredictability in the art, and the lack of disclosure and guidance provided in the specification and in the prior art, it would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed. Response to Remarks:
The response argues:
“The specification describes that the biomarkers for diagnosing age-related decline in ovarian reserve, supported by the use of naturally aged models in paragraph [0064] and the diagnosis of early ovarian failure in paragraph [0086]. The use of miR-145-5p and miR-425- 5p to determine whether a female subject has high/low ovarian reserve or high/low activation of ovarian function is disclosed in paragraphs [0034], [0077]-[0078], and [0086].”
These arguments have been fully consdiered but are not persuasive. The specification does not in fact teach the diagnosis of age-related decline in ovarian reserve and early ovarian failure. Rather, para [0086] asserts that changes in the expression level of miR-145-5p and miR-425-5p in blood samples may be used as a marker of follicle development to predict ovarian reserve in women or to “predict ovarian function, such as hormone production, and be used as a marker for diagnosis of early ovarian failure.” However, the results provided in the specification do not establish that one can use the recited methods for these diagnostic purposes. The specification teaches assaying serum samples from 52-week old mice who received human placenta-derived mesenchymal stem cell injections and reports that miR-425-5p was overexpressed and miR-145-5p was decreased in the serum of the mice who received the human placenta-derived mesenchymal stem cells injections as compared to control mice (para [0078]). It is unclear as to how these teachings establish that it is predictable to diagnose an age-related decline in ovarian reserve in a female human subject or any non-human female subject by measuring the expression level of miR-145-5p and miR-425-5p in any sample from the subject and determining that the subject has high ovarian reserve or high activation of ovarian function when the measured expression level of the miR-145-5p is decreased or the level of miR-425-5p is decreased as compared to a control sample, or determining that the subject has a low risk of early ovarian failure when the measured expression level of the miR-145-5p is decreased or the measured level of miR-425-5p is increased as compared to a control level, wherein the ovarian reserve indicates whether or not there is activation of primordial follicles, production of ovarian hormones, or ovarian hypofunction. Note that the specification does not teach the level of miR-145-5p and miR-425-5p in serum or other samples from female subjects at earlier stages in life with a high ovarian reserve and at later stages in life with a lower ovarian reserve so as to establish that changes in the levels of these miRNAs are correlated with age-related decline in ovarian reserve.
Note also that the rejection discussed the unpredictability of extrapolating the results set forth in the specification with serum samples obtained from mice injected with hPD-MSCs to any sample obtained from any subject. The rejection cited Battaglia as reporting that miR-425-5p (and miR-145) expression levels in human oocytes varied significantly within the samples analyzed from both young and old oocytes (see “Results” at p. 4 and Table 1 “Unsteadily expressed”); and that miR-425-5p (and miR-145-5p) were not identified by Battaglia as one of the miRNAs that were differentially expressed between old and young oocytes. Further, the rejection addressed the unpredictability of detecting the level of miR-425-5p (and miR-145-5p) in samples by performing one of the protein assays of immunoblotting, enzyme-linked immunosorbent assay (ELISA), immunohistochemical staining, protein chip, or immunoprecipitation assay, as encompassed by claim 11. The response does not appear to specifically address these aspects of the rejection.
The rejection is maintained for the reasons of record.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682