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 application has been transferred to Examiner Haney in Art Unit 1682.
3. Applicant’s election with traverse of: protein, blastocoel fluid, trophectoderm, abnormal placentation, human, and Fragile X syndrome in the reply filed on October 20, 2025 is acknowledged. The traversal is on the groups that additional species could be searched without an undue burden.
This argument has been fully considered. The following election of species requirements have been withdrawn: Group I (analytes), Group II (sample source), and Group VI (disease). The following election of species requirements have been maintained: Group III (embryo cell type), Group IV (outcome), and Group V (subject). The Examiner does not agree that the members of these groups could be searched without undue burden because the members of these groupings require different searches that are not co-extensive. For instance, a literature search for one species is not co-extensive with a literature search for the other species. For instance, a finding that, for example, one species is anticipated or obvious over the prior art would not necessarily extend to a finding that each of the other species are also anticipated or obvious over the prior art. Similarly, a finding that one species is novel and unobvious over the prior art would not necessarily extend to a finding that all the other species are also novel and unobvious over the prior art. Accordingly, examination of these distinct species does pose a serious burden on the examiner and therefore the election of species requirement is proper.
Claims 1-20, 23-24, and 26 are currently pending.
Claims 6-7 and 20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on October 20, 2025.
Claim Rejections - 35 USC § 101
4. 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 1-5, 8-19, 23-24, and 26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. The claims recite a judicial exception that is not integrated into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The claim analysis is set forth below.
Step 1: The claims are directed to the statutory category of a process.
Step 2A, prong one: Evaluate Whether the Claim Recites a Judicial Exception
The instant claims recite a law of nature.
The claims recite a correlation between the expression level of PAPPA and risk of adverse obstetric outcomes (abnormal placentation, spontaneous miscarriage, small for gestational age (SGA), intrauterine growth restriction (IUGR), intrauterine fetal demise (IUFD), or pre- eclampsia). This type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo.
The instant claims recite an abstract idea.
The claims recite a step of “selecting” an embryo for implantation into a mammalian subject (clm 15). The “selecting” step broadly encompasses a mental processes. For example, one may “select” an embryo for implantation by thinking about the level of PAPPA that was detected in the measuring step. Mental processes, which are concepts performed in the human mind (including observation, evaluation, judgment, opinions) are considered to be abstract ideas.
Step 2A, prong two: Evaluate Whether the Judicial Exception Is Integrated Into a Practical Application
The claims do NOT recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). For example, the claims do not practically apply the judicial exception by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
An additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing; and
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological
environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
Claim 16 recites “wherein the embryo is implanted into the mammalian subject as part of an in vitro fertilization method”. The claims broadly encompass implanting the embryo into subjects with high risk and subjects with low risk. The implanting does not apply the exception in anyway because all subjects get implanted regardless of their level of risk. Thus the implanting does not integrate the judicial exceptions into a practical application.
In addition to the judicial exceptions the claims recite steps of obtaining in vitro an embryo at the blastocyst stage of development and measuring the expression of PAPPA in one or more embryo cells, in the blastocoel fluid, and/or in embryo culture fluid that has been used to store or culture the embryo. These steps are not considered to integrate the judicial exception into a practical application because they merely add insignificant extra-solution activity (data gathering) to the judicial exception.
Step 2B: Evaluate Whether the Claim Provides an Inventive Concept
In addition to the judicial exceptions the claims recite steps of obtaining in vitro an embryo at the blastocyst stage of development and measuring the expression of PAPPA in one or more embryo cells, in the blastocoel fluid, and/or in embryo culture fluid that has been used to store or culture the embryo. These steps do not amount to significantly more because they simply append well understood, routine, and conventional activities previously known in the art, specified at a high level of generality, to the judicial exceptions.
The steps are recited at a high level of generality. For example the step of measuring the expression of PAPPA merely instructs one to perform any type of mRNA or protein expression analysis. When recited at this high level of generality, there is no meaningful limitation that distinguishes this step from well understood, routine, and conventional activities engaged in by scientists prior to applicants invention and at the time the application was filed. It is noted that claims 10-13 recite specific assays for measuring PAPPA, however these claims do nothing more than spell out what practioners already knew-how to measure expression using routine, ordinary techniques. Nothing is added by identifying the techniques to be used because these techniques were the well understood, routine, and conventional techniques that a scientist would have thought of when instructed to measure gene expression.
Additionally the prior art also demonstrates the well understood, routine, conventional nature of additional elements because it teaches that the additional elements are well known or commercially available.
For example Jaroudi (Human Reproduction Vol 24 No 10 pages 2649-2655, 2009) teaches gene expression analysis was investigated in human oocytes and blasotcysts using the Human Genome Survey Microarrays V2.0 (Applied Biosystems) (abstract). It is noted that this particular microarray has probes which detect PAPPA.
Further it is noted 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.
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);
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);
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);
Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
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)
For the reasons set forth above the claims are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 112(a)
5. 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 1-5, 8-19, 23-24, and 26 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
An in vitro method of screening an embryo, comprising:
(i) obtaining in vitro an embryo at the blastocyst stage of development, and
(ii) measuring the expression of pregnancy-associated plasma protein-A (PAPPA) in one or more embryo cells, in the blastocoel fluid, and/or in embryo culture fluid that has been used to store or culture the embryo.
does not reasonably provide enablement for the claims as broadly written. 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.
Scope of the Claims/Nature of the Invention
The claims are drawn to an in vitro method of screening an embryo.
The claims recite a first step of obtaining in vitro an embryo at the blastocyst stage of development.
The claims recite a second step of measuring the expression of pregnancy-associated plasma protein-A (PAPPA) in one or more embryo cells, in the blastocoel fluid, and/or in embryo culture fluid that has been used to store or culture the embryo. The claims broadly encompass measuring the amount of PAPPA mRNA or protein. The claims broadly encompass three sample types: (i) embryo cells, (ii) blastocoel fluid, and (iii) embryo culture fluid. The recitation of “embryo cells” broadly encompasses trophoblast cells, trophectoderm cells, syncytiotrophoblast cells, inner cell mass cells etc.
The claims recite a final wherein clause stating that a decreased expression of PAPPA below a control level indicates an increased risk of an adverse obstetric outcome if the embryo is implanted into a mammalian subject. In view of the recitation of the phrase “control level” the claims broadly encompass ANY control level. The control level could be the level of PAPPA or another gene in ANY type of sample (serum, follicular fluid, embryo cells, etc.) obtained from ANY type of subject (those who carried full term, those who had gestational diabetes, those who miscarried, etc.). Further in view of the recitation of “adverse obstetric outcome” the claims broadly encompass ANY type of adverse obstetric outcome (i.e., preeclampsia, gestational diabetes, preterm birth, still birth, postpartum hemorrhage). Claim 8 states that the adverse obstetric outcome is abnormal placentation, spontaneous miscarriage, small for gestational age (SGA), intrauterine growth restriction (IUGR), intrauterine fetal demise (IUFD), or pre- eclampsia. Finally in view of the recitation of “mammalian” the claims broadly encompass both human and non-human mammals.
The nature of the invention requires a reliable correlation between the level of PAPPA mRNA or protein in an embryo cell, blastocoel fluid, or embryo culture fluid sample obtained from ANY mammalian subject and risk of ANY type of adverse obstetric outcome.
Teachings in the Specification and Examples
The specification (para 0040) teaches that blastocoelic fluid conditioned media (BFCM) was obtained from blastocyst stage embryos following standard, routine controlled ovarian stimulation and subsequent IVF processes.
The specification (para 0042) teaches that RT-qPCR was performed for PAPP-A. Blastocoel fluid-conditioned media from individual euploid pre-implantation embryos were assessed for RNA content using a RNA 6000 Pico Kit with an Agilent 2100 Bioanalyzer. Individual samples were treated with RNase-free DNase 1 for 30 minutes at 37° C. followed by heat inactivation. Samples were then subjected to cDNA synthesis with a High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems) per manufacturer's instructions. cDNA quantity was then determined with a High Sensitivity DNA Kit with an Agilent 2100 Bioanalyzer. cDNA was then combined with 2×TaqMan Master Mix, 20×Gene Expression Assay (GAPDH and PAPP-A specific) and RNase-free water per manufacturer's instructions (Applied Biosystems). Duplicate reactions for each sample were run for each gene of interest using a 7500 Fast Real-Time PCR System (Applied Biosystems, USA) at 50° C. for 2 minutes, 95° C. for 20 seconds, followed by 40 cycles of 95° C. for 3 seconds and 60° C. for 30 seconds.
The specification (para 0044) teaches that a sample size of 80 trophectoderm-tested euploid Day 5 good quality blastocysts from 36 patients that underwent IVF/ICSI/PGT-A/freeze-all had BFCM analyzed for PAPP-A mRNA expression. PAPP-A mRNA was detected in 45 of 80 BFCM samples (56.3%), with varying levels of expression across samples The results are presented in Tables 1, 2, and 3. Table 3 is partially reproduced below:
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The specification notes that the expression in B18 is 16.19 times more than in B23, and expression in B18 is 9.23 times more than in B28.
The specification (para 0049) teaches that the expression of PAPP-A was observed in the BFCM of preimplantation blastocyst stage embryos in vitro. Larger prospective studies can be performed and are underway regarding PAPP-A expression at the level of human blastocyst stage embryo and maternal/fetal pregnancy outcomes of trophectoderm-tested euploid blastocyst transfer. It is anticipated that additional data showing that PAPP-A in BFCM and/or biopsied embryonic cells can predict adverse obstetric outcomes. These approaches may be used in the process of embryo selection, in addition to euploid status. In this way, these methods may be used to optimize or improve the potential or probability of live birth for IVF patients.
State of the Art and the Unpredictability of the Art
While methods of measuring biomarkers are known in the art, methods of correlating biomarkers with a phenotype (such as adverse obstetric outcomes) are highly unpredictable. The unpredictability will be discussed below.
The claims broadly encompass being able to use the level of PAPPA in one or more embryo cells, in the blastocoel fluid, and/or in embryo culture fluid that has been used to store or culture the embryo to detect adverse obstetric outcomes. The adverse obstetric outcome can be abnormal placentation, spontaneous miscarriage, small for gestational age (SGA), intrauterine growth restriction (IUGR), intrauterine fetal demise (IUFD), or pre- eclampsia. The specification does not provide support for this. There is no evidence of a correlation between PAPPA and ANY adverse obstetric outcome. At best the specification teaches that “It is anticipated that additional data showing that PAPP-A in BFCM and/or biopsied embryonic cells can predict adverse obstetric outcomes.”. However this is a prophetic statement that is not supported by any factual evidence. In the absence of evidence to the contrary it is highly unpredictable if PAPPA is actually correlated with any type of adverse obstetric outcome.
The claims broadly encompass a method of detecting an increased risk for an adverse obstetric based on the expression level of PAPPA in ANY type of embryo cell (trophoblast cells, trophectoderm cells, syncytiotrophoblast cells, inner cell mass cells etc.). However the specification only discloses the level of PAPPA in trophectoderm cells. It is highly unpredictable if the level of PAPPA observed in trophectoderm cells can be extrapolated to other sample types encompassed by the claims. The prior art of Ozawa (BMC Developmental Biology 2012 12:33) teaches that they determined, for the first time, global gene expression patterns in the ICM and TE isolated from bovine blastocysts. A total of 870 genes were differentially expressed between ICM and TE. Several genes characteristic of ICM (for example, NANOG, SOX2, and STAT3) and TE (ELF5, GATA3, and KRT18) in mouse and human showed similar patterns in bovine. Other genes, however, showed differences in expression between ICM and TE that deviates from the expected based on mouse and human (abstract). Thus in the absence of evidence to the contrary it is highly unpredictable if the PAPPA expression levels observed trophectoderm cells will be the same in other types of embryo cells.
Additionally it is relevant to point out the unpredictability as to whether or not a measure of RNA expression is indicative of the level of protein in a sample. Chan (G&P magazine 2006 Vol 6 No 3 pages 20-26). teaches that cells have elaborate regulatory mechanisms at the level of transcription, post-transcription, and post-translation (p.1, last paragraph), and that transcript and protein abundance measurements may not be concordant (p.3, sixth full paragraph). Thus it is unpredictable as to whether or not the results pertaining to RNA expression, as presented in the instant specification, would be applicable to methods requiring or encompassing the analysis of protein expression.
Because the claims encompass the analysis of ANY type of mammal, whereas the instant specification provides analysis of only human samples, it is relevant to point out that there is a large amount of unpredictability with regard to comparing results from gene expression analysis data in humans to other even closely related animals. Hoshikawa et al (Physical Genomics 2003 Vol 12 pages 209-219) teaches unpredictability with regard to applying gene expression results among different organisms. The reference teaches the analysis of gene expression in lung tissue in response to hypoxic conditions which lead to pulmonary hypertension (Fig. 1). The reference teaches that the gene expression profile in mouse is different from that observed in rat (Tables 1-4; p.209 - Abstract). Thus it is not predictable that the findings with respect to human PAPPA could be extrapolated to ANY other mammal.
Finally it is highly unpredictable if the claimed method can be practiced using ANY control level. The claims broadly encompass a control level that could be the level of PAPPA or another gene in ANY type of sample (serum, follicular fluid, embryo cells, etc.) obtained from ANY type of subject (those who carried full term, those who had gestational diabetes, those who miscarried, etc.). However the teachings in the specification are limited to the analysis of PAPPA in blastocoelic fluid conditioned media (BFCM) obtained from blastocyst stage embryos from subject who got pregnant to those who did not. It is highly unpredictable if the PAPPA will be differentially expressed when compared to ANY control level encompassed by the claims.
Quantity of Experimentation:
The quantity of experimentation necessary is great, on the order of many man-years, and then with little if any reasonable expectation of successfully enabling the full scope of the claims. In support of this position, it is noted that the claimed methods encompass being able to use the level of PAPPA in one or more embryo cells, in the blastocoel fluid, and/or in embryo culture fluid that has been used to store or culture the embryo to detect adverse obstetric outcomes. The adverse obstetric outcome can be abnormal placentation, spontaneous miscarriage, small for gestational age (SGA), intrauterine growth restriction (IUGR), intrauterine fetal demise (IUFD), or pre- eclampsia.
In order to practice the breadth of the claimed invention one of skill in the art would first have to recruit patients willing to provide samples from embryo cells, blastocoel fluid, and/or in embryo culture fluid. Then PAPPA mRNA and protein levels would have to be detected in the samples. Then those patients would have to be followed over time to see if they had normal pregnancies or if they developed a representative number of different adverse obstetric outcomes. Then all the data would need to be analyzed to determine if PAPPA is differentially expressed between the samples obtained from the normal pregnancies and the samples obtained for each of the different adverse obstetric outcomes. The analysis would have to include both human and non-human mammals. The specification has merely provided an invitation for further experimentation. The results of such experimentation are highly unpredictable.
The amount of experimentation that would be required to practice the full scope of the claimed invention and the amount of time and cost this experimentation would take supports the position that such experimentation is undue. Attention is directed to Wyeth v. Abbott Laboratories 107 USPQ2d 1273, 1275, 1276 (Fed. Cir. June 2013):
Claims are not enabled when, at the effective filing date of the patent, one of ordinary skill in the art could not practice their full scope without undue experimentation. MagSil Corp. v. Hitachi Global Storage Techs., Inc., 687 F.3d 1377, 1380-81 [103 USPQ2d 1769] (Fed. Cir. 2012).
The remaining question is whether having to synthesize and screen each of at least tens of thousands of candidate compounds constitutes undue experimentation. We hold that it does. Undue experimentation is a matter of degree. Chiron Corp. v. Genentech, Inc., 363 F.3d 1247, 1253 [70 USPQ2d 1321] (Fed. Cir. 2004) (internal quotation omitted). Even “a considerable amount of experimentation is permissible,” as long as it is “merely routine” or the specification “provides a reasonable amount of guidance” regarding the direction of experimentation. Johns Hopkins Univ. v. CellPro, Inc., 152 F.3d 1342, 1360-61 [47 USPQ2d 1705] (Fed. Cir. 1998) (internal quotation omitted). Yet, routine experimentation is “not without bounds.” Cephalon, Inc. v. Watson Pharm., Inc., 707 F.3d 1330, 1339 [105 USPQ2d 1817] (Fed. Cir. 2013). (Emphasis added)
In Cephalon, although we ultimately reversed a finding of nonenablement, we noted that the defendant had not established that required experimentation “would be excessive, e.g., that it would involve testing for an unreasonable length of time.” 707 F.3d at 1339 (citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] (Fed. Cir. 1983)). Finally, in In re Vaeck, we affirmed the PTO's nonenablement rejection of claims reciting heterologous gene expression in as many as 150 genera of cyanobacteria. 947 F.2d 488, 495-96 [20 USPQ2d 1438] (Fed. Cir. 1991). The specification disclosed only nine genera, despite cyanobacteria being a “diverse and relatively poorly understood group of microorganisms,” with unpredictable heterologous gene expression. Id. at 496. (Emphasis added)
Additionally, attention is directed to Cephalon at 1823, citing White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 218 USPQ 961, that work that would require 18 months to 2 years so to enable the full scope of an invention, even if routine, would constitute undue experimentation. As stated therein:
Permissible experimentation is, nevertheless, not without bounds. This court has held that experimentation was unreasonable, for example, where it was found that eighteen months to two years’ work was required to practice the patented invention. See, e.g., White Consol. Indus., Inc. v. Vega Servo-Control, Inc., 713 F.2d 788, 791 [218 USPQ 961] Fed. Cir.1983). (Emphasis added)
Attention is also directed to MPEP 2164.06(b) and In re Vaeck, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991).
Where, as here, a claimed genus represents a diverse and relatively poorly understood group of microorganisms, the required level of disclosure will be greater than, for example, the disclosure of an invention involving a “predictable” factor such as a mechanical or electrical element. See Fisher, 427 F.2d at 839, 166 USPQ at 24.
In view of such legal precedence, the aspect of having to work for so many years just to provide the starting materials for minute fraction of the scope of the claimed invention is deemed to constitute both an unreasonable length of time and undue experimentation.
Conclusions:
Herein, although the level of skill in the art is high, given the lack of disclosure in the specification and in the prior art and the unpredictability of the art, it would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed.
Claim Rejections - 35 USC § 102
6. 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.
Claims 1, 4-5, 9-10, 12-19, 23-24, and 26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sanyal (US 2018/0064425 Pub 3/8/2018).
Regarding Claims 1, 4, and 5 Sanyal teaches a method of retrieving preimplantation stage embryos of the uterus of a subject (para 0045). Sanyal teaches that the preimplantation embryo is a blastocyst (para 0046). Sanyal teaches that a trophectoderm biopsy is performed on the retrieved preimplantation embryo (para 0059). Sanyal teaches determining the level of PAPPA protein and RNA in the retrieved biological material (para 0040). Thus Sanyal teaches a method comprising obtaining in vitro an embryo at the blastocyst stage of development, and measuring the expression of pregnancy-associated plasma protein-A (PAPPA) in one or more embryo cells. While Sanyal teaches all of the claimed method steps, Sanyal does not teach a correlation between PAPPA and risk of an adverse obstetric condition. However this art rejection is set forth because it teaches a broad interpretation of the claims which does not require such a correlation. In the instant case the claims recite a “wherein” clause stating that “decreased expression of PAPPA below a control level indicates an increased risk of an adverse obstetric outcome if the embryo is implanted into a mammalian subject”. However, Applicants are reminded that claim scope is not limited by claim language (such as wherein clauses) that suggests or makes optional but does not require steps to be performed. This rejection could be overcome by amending the claim to recite an active process step of requiring the correlation.
Regarding Claims 9, 10, 12, and 13 Sanyal teaches determining the level of PAPPA protein and RNA in the retrieved biological material (para 0040). Sanyal teaches that the biological samples collected using the devices and methods of the invention are analyzed for the presence of biomarkers by methods well known in the art, for example, analysis of cellular parameters by multispectral immunocytochemistry, quantitative PCR and microanalysis of nucleic acids, and microarray and ELISA analysis of protein biomarkers (para 0091).
Regarding Claims 14, 24, and 26 Sanyal teaches the retrieved preimplantation embryos are analyzed by preimplantation genetic diagnosis (PGD) to detect an anomaly of the genome, for example, an anomaly associated with a disorder selected from the group consisting of: cancer, neural disorders, muscular disorders, cardiovascular disorders, Down syndrome, muscular dystrophy, cystic fibrosis and Tay Sachs disease (para 0055). It is noted that a test for Down syndrome would be a test for an aneuploidy.
Regarding Claim 15 Sanyal teaches that retrieved preimplantation embryos that are not identified as having an anomaly of the genome are transferred to the subject for in utero development, donated or used for surrogacy (para 0057). Thus Sanyal teaches a method of selecting an embryo for implantation into the mammalian subject.
Regarding Claims 16-19 and 23 Sanyal teaches a method wherein the embryo is implanted into a subject as part of an in vitro fertilization (IVF) method. Sanyal teaches that mature oocytes are retrieved from the ovary of women treated with gonadotrophins, they are then fertilized by sperm in vitro, and grown into morula of multiple blastomeres (cells), and finally into a hollow ball of cells, blastocysts. Such embryos are then transferred to the receptive uterus for implantation, pregnancy and further growth and development (para 0144). Sanyal teaches that retrieved preimplantation embryos that are not identified as having an anomaly of the genome are transferred to the subject for in utero development, donated or used for surrogacy (para 0057).
Claim Rejections - 35 USC § 103
7. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
8. Claims 2 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Sanyal (US 2018/0064425 Pub 3/8/2018) and Li (Scientific Reports 2018 8:9275).
The teachings of Sanyal are presented above.
Sanyal does not teach a method wherein the expression of PAPPA is measured in blastocoel fluid or embryo culture fluid.
However Li teaches that they performed preimplantation genetic screening with spent culture medium/ blastocoel fluid (abstract).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Sanyal by detecting the expression of PAPPA in spent culture medium/ blastocoel fluid as suggested by Li for the benefit of having a less invasive way to conduct preimplantation genetic screening.
9. Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Sanyal (US 2018/0064425 Pub 3/8/2018) and Singh (Int J Adv Res BiolSci 1(7) 2014 pages 65-80).
The teachings of Sanyal are presented above.
Sanyal does not teach a method wherein the reverse transcription-polymerase chain reaction (RT-PCR) is quantitative.
However Singh quantitative reverse transcription PCR (page 75).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Sanyal by measuring PAPPA expression using quantitative reverse transcription PCR as suggested by Singh. The claim would have been obvious because the substitution of one assay for measuring gene expression or another would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
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/AMANDA HANEY/ Primary Examiner, Art Unit 1682