DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-9, 14-20, 22 and 23 are pending in this application and were examined on their merits.
The rejection of Claims 1-9, 14-20, 22 and 23 under 35 U.S.C. § 103 as being
unpatentable over Wu et al. (2015), cited in the IDS, and further in view of Kuznyetsov
et al. (2017), has been withdrawn due to the Applicant’s amendments to the claims filed 01/14/2026.
Claim Rejections - 35 USC § 103
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.
Claims 1-9, 14-20, 22 and 23 are rejected under 35 U.S.C. § 103 as being
unpatentable over Wu et al. (2015), cited in the IDS, and further in view of Kuznyetsov
et al. (2017) and Xu et al. (2016).
Wu et al. teaches a method comprising:
culturing fertilized oocytes (blastocysts) from Day 1-Day 3 in a first cleavage stage culture medium (G1) (Pg. 3, Lines 8-9);
then a second stage of culturing from Day 3-Day 5 in a blastocyst culture
medium (G-2) (Pg. 3, Lines 18-19);
transferring the Day 5 blastocysts into a second culture system comprising fresh
G-2 culture medium and culturing for a time T1 to Day 6 followed by microscopic zona
(pellucida) ablation (perforation) (Pg. 3, Lines 22-26);
collecting the spent, cell-free blastocyst culture medium and performing a genetic
test to identify the health status (α-thalassemia) of the blastocyst with a diagnosis
efficiency (accuracy) rate of 82.1% (Pg. 3, Lines 26-27 and Pg. 1, Abstract and Pg. 5,
Lines 9-10), and reading on Claims 1, 8 and 20.
With regard to Claim 20, Wu et al. teaches transferring the Day 5 blastocysts into
a second culture system comprising fresh G-2 culture medium and culturing for a time
T1 to Day 6 followed by microscopic zona (pellucida) ablation (perforation) (Pg. 3, Lines
22-26); collecting the spent, cell-free blastocyst culture medium and performing a
genetic test to identify the health status (α-thalassemia) of the blastocyst with a
diagnosis efficiency (accuracy) rate of 82.1% (Pg. 3, Lines 26-27 and Pg. 1, Abstract
and Pg. 5, Lines 9-10).
Wu et al. further teaches optimizing the procedure to quantitatively assess DNA
concentration in the blastocyst culture media over time wherein a diagnosis efficiency of
94% and 96% were obtained at Day 5 and Day 6, respectively (indicative of the
criticality of this time period) (Pg. 10, Lines 21-22 and 27-28).
With regard to Claims 2-5, the Wu et al. reference teaches culturing fertilized
oocytes (blastocysts) from Day 1-Day 3 in a first cleavage stage culture medium (G1)
(Pg. 3, Lines 8-9); then a second stage of culturing from Day 3-Day 5 in a blastocyst
culture medium (G-2) (Pg. 3, Lines 18-19);
transferring the Day 5 blastocysts into a second culture system comprising fresh
G-2 culture medium and culturing for a time T1 to Day 6 followed by microscopic Zona
(pellucida) ablation (perforation) (Pg. 3, Lines 22-26).
With regard to the limitations of Claim 7, it would be inherent in the method of Wu
et al. that the accuracy rate is greater than or equal to 80%, as exemplified by the
obtained diagnosis efficiency (accuracy) rate of 82.1%, noted above.
With regard to Claims 14-17 and 19, Wu et al. teaches transferring the Day 5
blastocysts into a second culture system comprising fresh G-2 culture medium and
culturing for a time T1 to Day 6 followed by microscopic zona (pellucida) ablation
(perforation) (Pg. 3, Lines 22-26); and collecting the spent, cell-free blastocyst culture
medium and performing a genetic test to identify the health status (α-thalassemia) of the
blastocyst with a diagnosis efficiency (accuracy) rate of 82.1% (Pg. 3, Lines 26-27 and
Pg. 1, Abstract and Pg. 5, Lines 9-10).
With regard to Claim 18, the Examiner notes that Wu et al. teaches transferring
the Day 5 blastocysts into a second culture system comprising fresh G-2 culture
medium and culturing for a time T1 to Day 6 followed by microscopic Zona ablation
(perforation) (Pg. 3, Lines 22-26).
The teachings of Wu et al. were discussed above.
Although Wu et al. teaches the culturing of transferred later stage blastocysts
from Day 5 to Day 6 (potentially an 8 [to 12] hour period) before collecting a spent
culture medium sample, the reference did not specifically teach a method wherein the
T1 time is 3-6 hours, as required by Claims 1 and 8;
performing a copy number variation (CNV) assay to identify the health status of
the blastocyst, wherein the method has a low false negative rate of less than 8%, as now required by Claim 1;
further including a culture module for a later stage blastocyst, functioning to
exchange the medium of the cultured blastocyst on Day 5 to Day 6, and to perform the
later stage culture of the blastocyst for a period of time T1, as required by Claim 9;
wherein the T1 time is 3-5 hours, as required by Claim 6;
or wherein the accuracy rate is greater than or equal to 85% or 90%, as
required by Claims 22 and 23.
Xu et al. teaches collecting spent blastocyst culture media and performing genetic analysis to identify chromosomal abnormalities of the blastocyst (Pgs. 11911-11912, Materials and Methods) wherein the method had a false negative rate of 11.8%, noting that in the future the false-negative rate could be further minimized by carefully and thoroughly removing all cumulus cells before embryo culture (Pg. 11909, Column 2, Lines 27-29 and Pg. 11910, Column 1, Lines 1-7).
Kuznyetsov et al. teaches a method wherein Day 5/6 blastocysts are transferred
into fresh medium and cultured for 24 hours, before collecting the spent blastocyst
culture medium for copy number variation genetic analysis to determine the health
status of the blastocyst (Pg. e277, P-444).
While the references listed above do not specifically teach the limitation of Claim
1, that the method has a false negative rate of less than 8%, one of ordinary skill in the art would recognize that the false negative rate is a result-effective optimizable variable. For example, Xu et al. teaches analysis of spent blastocyst culture media for chromosomal abnormalities which has a false negative rate of 11.8% and suggests the rate can be further reduced. Thus, the art establishes that the false negative rate in the genetic analysis of spent blastocyst media is a result-effective variable. This is motivation for someone of ordinary skill in the art to optimize the false negative rate by routine experimentation to find those that are functional or optimal to produce a false negative rate which then would be inclusive or cover the instantly claimed values. Absent any teaching of criticality by Applicant concerning the method false negative rate, it would be prima facie obvious that one of ordinary skill in the art would recognize this limitation is an optimizable variable which can be met as a matter of routine optimization, see MPEP § 2144.05, II, B. Those of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to make this modification in order to produce a spent blastocyst media analysis method which has a false negative rate which is as low as possible. There would have been a reasonable expectation of success in making these modifications because at least both of the Wu et al. and Xu et al. references are reasonably drawn to the same field of endeavor, that is, the collection of spent culture medium from late stage blastocysts for genetic analysis.
While the references listed above do not specifically teach the limitation of Claim
8, that the T1 time is 3-6 hours, one of ordinary skill in the art would recognize that the
culturing time is a result-effective optimizable variable. For example, Kuznyetsov et al.
teaches culturing transferred later stage Day5/6 blastocysts for 24 hours before
collecting a spent culture medium sample while Wu et al. teaches the culturing of
transferred later stage blastocysts from Day 5 to Day 6 (potentially an 8-12 hour time)
before collecting a spent culture medium sample. Thus, the art establishes that the incubation time to obtain spent blastocyst media for analysis is a result-effective variable. This is motivation for someone of ordinary skill in the art to practice or test incubation times widely to find those that are functional or optimal to sufficiently provide a suitable sample of spent blastocyst culture medium for analysis which then would be inclusive or cover the instantly claimed values. Absent any teaching of criticality by Applicant concerning the T1 culture time, it would be prima facie obvious that one of ordinary skill in the art would recognize this limitation is an optimizable variable which can be met as a matter of routine optimization, see MPEP § 2144.05, II, B. Those of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to make this modification in order to obtain a relevant blastocyst spent culture medium. There would have been a reasonable expectation of success in making these modifications because at least both of the Wu et al. and Kuznyetsov et al. references are reasonably drawn to the same field of endeavor, that is, the collection of spent culture medium from late stage blastocysts for genetic analysis.
With regard to Claim 9, it would have been obvious to those of ordinary skill in
the art to modify the method of Wu et al. which comprises culturing a later stage
blastocyst, exchanging the culture medium on Day 5 to Day 6 and culturing the
blastocyst for a period of time to include a module/apparatus for performing those steps
because this is no more than the automation of a previously manual activity. See the
MPEP at 2144.04, B. III. Those of ordinary skill in the art would have been motivated to
make this modification in order to automatically perform the culture steps and eliminate
the need to do so by hand. There would have been a reasonable expectation of
success in making this modification because Wu et al. already teaches a manual
process of performing the claimed method steps and the automation thereof is prima
facie obvious.
While the references listed above do not specifically teach the limitation of
Claims 22 and 23, that the accuracy rate is greater than or equal to 85% or 90%
respectively, one of ordinary skill in the art would recognize that the accuracy rate is a
result-effective optimizable variable. Wu et al. teaches optimizing the procedure to quantitatively assess DNA concentration in spent culture media over time wherein a diagnosis efficiency of 94% and 96% were obtained at Day 5 and Day 6, respectively (Pg. 10, Lines 21-22 and 27-28). This is motivation for someone of ordinary skill in the art to practice or test different culture incubation times widely to find those that are functional or optimal to sufficiently provide a suitable sample of spent blastocyst culture medium for analysis providing the highest accuracy which then would be inclusive or cover the instantly claimed values.
Absent any teaching of criticality by the Applicant concerning the accuracy rate, it would be prima facie obvious that one of ordinary skill in the art would recognize this limitation is an optimizable variable which can be met as a matter of routine optimization, see MPEP § 2144.05, II, B. Those of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to make this modification in order to obtain a blastocyst spent culture medium which would provide the most accurate diagnosis. There would have been a reasonable expectation of success in making these modifications because the reference teaches the optimization of a similar method to achieve increased accuracy results.
Response to Arguments
Applicant’s arguments, see Remarks, filed 01/14/2026, with respect to the rejection(s) of claim(s) 1-9, 14-20, 22 and 23 under 35 U.S.C. § 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Wu et al. (2015), cited in the IDS, and further in view of Kuznyetsov et al. (2017) and Xu et al. (2016) as set forth above.
Applicant's arguments filed 01/14/2026 have been fully considered but they are not persuasive.
The Applicant argues that Wu teaches that the detectable ratio increased to 90.16% at Day 5 and 88.46% at Day 6 which is not statistically significant and notes the reference teaches it is advantageous to use samples with higher DNA concentration (Remarks, Pg. 5, Lines 21-30 and Pg. 6, Lines 1-3).
This is not found to be persuasive for the following reasons, as noted by Applicant the difference between Day 5 and Day 6 cell-free medium in diagnosis efficiency is negligible, and there is no teaching away from using Day 6 media. Thus, the ordinary artisan would recognize that either Day 5 or Day 6 media may be used in the diagnostic method to achieve the desired high diagnosis efficiency.
The Applicant argues that Kuznyetsov allegedly does not exchange medium for Day5/6 blastocysts but just warms the cryopreserved cells and puts them into fresh media an allegedly different process from that claimed (Remarks, Pg. 6, Lines 4-12).
This is not found to be persuasive for the following reasons, as discussed above,
Wu et al. teaches transferring the Day 5 blastocysts into a second culture system comprising fresh G-2 culture medium and culturing for a time T1 (potentially 8-12 hours) to Day 6 followed by microscopic zona (pellucida) ablation (perforation) (Pg. 3, Lines 22-26);
and collecting the spent, cell-free blastocyst culture medium and performing a genetic test to identify the health status (a-thalassemia) of the blastocyst with a diagnosis efficiency (accuracy) rate of 82.1% (Pg. 3, Lines 26-27 and Pg. 1, Abstract and Pg. 5, Lines 9-10). The reference did not specifically teach the T1 time is 3-6 hours. Kuznyetsov taught wherein (presumably cryopreserved in some agent/media) Day5/6 blastocysts were warmed and placed into fresh medium (Global HP with HAS) for 24 hours before collection of the media for analysis. Thus, both Wu and Kuznyetsov place obtained Day 5/6 blastocysts into fresh culture media which is later collected for genetic analysis, contrary to Applicant’s assertion.
The Applicant argues that Wu does not disclose the claimed T1 time of 3-6 hours or the claimed false negative rate and Kuznyetsov does not remedy the alleged deficiencies of Wu (Remarks, Pg. 6, Lines 13-22 and Pg. 8, Lines 1-11).
This is not found to be persuasive for the following reasons, as discussed in the prior action and above, the T1 time and false negative rate are result effective, optimizable variables. For example, Kuznyetsov teaches culturing transferred later stage Day5/6 blastocysts for 24 hours before collecting a spent culture medium sample while Wu teaches the culturing of transferred later stage blastocysts from Day 5 to Day 6 (potentially an 8-12 hour time) before collecting a spent culture medium sample. Thus, the art establishes that the incubation time to obtain spent blastocyst media for analysis is a result-effective variable.
This is motivation for someone of ordinary skill in the art to practice or test incubation times widely to find those that are functional or optimal to sufficiently provide
a suitable sample of spent blastocyst culture medium for analysis which then would be
inclusive or cover the instantly claimed values. Similarly, Xu et al. teaches analysis of spent blastocyst culture media for chromosomal abnormalities which has a false negative rate of 11.8% and suggests the rate can be further reduced. Thus, the art establishes that the false negative rate in the genetic analysis of spent blastocyst media is a result-effective variable. This is motivation for someone of ordinary skill in the art to optimize the false negative rate by routine experimentation to find those that are functional or optimal to produce a false negative rate which then would be inclusive or cover the instantly claimed values.
The Applicant argues that the claimed method achieves the allegedly unexpected technical problem of reduced false negative rates (Remarks, Pgs. 6-7, Section II).
This is not found to be persuasive for the following reasons, the reduction in false positive rate is not “unexpected” as Xu et al. teaches that the false negative rate in spent blastocyst media genetic analysis is subject to experimental reduction by optimization.
The Applicant argues that with regard to diagnosis efficiency the genetic analysis of Wu and that of the instant invention are not comparable because Wu discloses oocytes fertilized with ICSI in which little exogenous contamination would occur as compared to other IVF methods in which exogenous contamination would be expected to be higher and to which the claimed invention is more applicable (Remarks, Pg. 8, Lines 12-19).
This is not found to be persuasive for the following reasons, in response to Applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which Applicant relies (i.e., IVF fertilization method and exogenous contamination) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, Applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Sharmila G Landau can be reached at (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/PAUL C MARTIN/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/ Supervisory Patent Examiner, Art Unit 1653