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 .
Status of the Claims
Claims 13-14, 22-23, 25, 27, and 32-33 are currently pending.
Claims 13-14, 25, and 27 have been amended.
Claims 1-12, 15-21, 24, 26, and 28-31 are or remain cancelled.
Claims 32 and 33 are newly added.
Claims 13-14, 22-23, 25, 27, and 32-33 have been considered on the merits.
Maintained Rejections Necessitated by Amendment
Claim Objections
Claims 13 and 14 are objected to because of the following informalities: the term “saturate” in lines 9, 11, and 12, of claims 13 and 14 needs to be amended to “saturated”. Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 13-14, 22-23, 25, and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Taft et al (Cold Spring Harbor Protocols, 2017; “In Vitro Fertilization in Mice”), in view of Merkel et al (US10844349B2), and Mirabi et al (Lipids in Health and Disease, 2017)..
With regards to claims 13 and 14, Taft teaches a method of performing artificial fertilization through the in vitro fertilization of mouse embryos (abstract). Taft teaches a method of adding albumin to a medium for artificial fertilization (pg. 887, lines 6-8), and adding into the medium sperm and an ovum to fertilize the ovum as required by claims 13 and 14 (pg. 889, see steps 7-10).
Regarding claims 22 and 23, Taft teaches a method of performing artificial fertilization through the in vitro fertilization of mouse embryos as required by claims 22 and 23 (abstract).
Taft teaches that the albumin used was BSA (pg. 887, lines 6-8), however Taft does not teach that the BSA was a “low caprylic acid-containing albumin” as required by claims 13 and 14.
Merkel discloses that they identified octanoic acid can be deleterious to mammalian cell culture and particularly stem cell cultures (col 2, para 1). Merkel teaches a method of use for an albumin formulation in the culturing of gametes or of embryos for assisted reproductive technologies (such as artificial fertilization or fertilization in vitro) (col. 13, para 2), the albumin formulation having less than 0.1-0.001 mM (i.e., 100-1 micromolar) concentration of caprylic acid (also known as octanoate) as required by claims 13 and 14 (col 6, para 6). Additionally, Merkel teaches multiple human embryonic stem cell cultures which are supplemented with varying levels of octanoate (a.k.a caprylic acid), and the octanoate concentrations of 0.2/0.5/1.0 mM (conversion: 2/5/10 μmol per gram of albumin) proved to maintain the embryonic stem cell doubling times at a normal level, whereas octanoate concentrations of 8.0 mM (conversion 80 μmol per gram of albumin) did not maintain the embryonic stem cells past the second passage (Col. 42-43, Table 25). Merkel also teaches that the formulation does not contain a level of octanoate which is sufficient to cause a deleterious effect on cells during in vitro culture (col 6, para 6).
One of ordinary skill in the art would find it obvious at the time of the effective filling date to combine the method of artificial fertilization taught by Taft with the low octanoate/ caprylic acid containing albumin for use in artificial fertilization technologies taught by Merkel to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Merkel teaches a method of use for an albumin formulation for the culture of gametes or embryos in assisted reproductive technologies (i.e. artificial fertilization or fertilization in vitro) (col. 13, para 2) and Merkel shows that low amounts (between 2-10 μmol) of octanoate/caprylic acid maintain embryonic stem cells, while higher amounts such as 80 μmol per gram of albumin do not support the embryonic stem cells adequately. One of ordinary skill in the art would have a reasonable expectation of success when making this modification because assisted reproductive technology is well known and straight forward procedurally (at least in mice) as exemplified by Taft and Merkel teaches the use of an albumin containing low octanoate/caprylic acid with gametes or embryos in these procedures.
Taft and Merkel do not teach that the composition contains either a saturated or unsaturated fatty acid, additionally, Taft and Merkel do not teach that the saturated or unsaturated fatty acid is chosen from pentadecanoic acid, palmitic acid, palmitoleic acid, margaric acid, stearic acid, or a mixture or salt thereof as required by claims 13 and 14. Taft and Merkel do not teach that the saturated or unsaturated fatty acid increases the rate of fertilization as compared to a medium for artificial fertilization without the fatty acid-added albumin or a medium for artificial fertilization comprising the low caprylic acid-containing albumin as required by claims 13 and 14. Taft and Merkel do not teach that the saturated or unsaturated fatty acid is chosen from the group of pentadecanoic acid, palmitic acid, and stearic acid or combinations thereof as required by claim 25 and 27. Taft and Merkel do not teach that the saturated or unsaturated fatty acid is chosen from the palmitic acid or stearic acid or a mixture thereof as required by claims 32 and 33.
However, Mirabi et al teaches a method of artificial fertilization which employs unsaturated fatty acids to counteract the harmful effects of saturated fatty acids on oocyte maturation and implantation. Mirabi teaches the method of artificial fertilization employs lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid are added as required by claims 13, 14, 25, 27, 32, and 33 (Table 2). Further, Mirabi teaches that higher concentrations of saturated fatty acids can have harmful effect on oocyte maturation and implantation, such effects can be counteracted by the presence of unsaturated fatty acids such as oleic acid (abstract, conclusion).
Based on the direct teaching of Mirabi that higher concentrations of saturated fatty acids can have a harmful effect of oocyte maturation and implantation (abstract, conclusion), in addition to the teachings of Merkel that lower caprylic acid concentrations are ideal for stem cell survival; one of ordinary skill in the art would read the conclusion of Mirabi that inclusion of unsaturated fatty acids can counteract the harmful effects seen with saturated fatty acids to demonstrate that “the saturated or unsaturated fatty acid increases the rate of fertilization as compared to a medium for artificial fertilization without the fatty acid-added albumin or a medium for artificial fertilization comprising the low caprylic acid-containing albumin”. Thus this result appears to be a direct effect of the combination of the cited art wherein the caprylic acid is added with an unsaturated fatty acid for the expressed purpose of counteracting the harmful effects of saturated fatty acids on oocyte maturation and implantation.
One of ordinary skill in the art would find it obvious at the time of the effective filling date to combine the artificial fertilization method taught by Taft and Merkel with the added fatty acids taught by Mirabi to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Mirabi teaches that higher concentrations of saturated fatty acids can have harmful effect on oocyte maturation and implantation, such effects can be counteracted by the presence of unsaturated fatty acids such as oleic acid (abstract, conclusion). One of ordinary skill in the art would have a reasonable expectation of success when making this modification because Taft and Merkel teach the necessary information regarding the use of the albumin media in assisted reproductive technologies, and Merkel and Mirabi both teach that the presence of saturated fatty acids have a harmful effect on embryos/embryonic stem cells.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, especially in the absence of evidence to the contrary.
Response to Declaration of Dr. Tatsuma Yao under C.F.R. 1.132
Dr. Yao describes at paragraphs 6-8 of the declaration that each art employed in the rejection does not on its own teach all of the limitations of the claims.
In response to Dr. Yao's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Therefore, the argument is not found persuasive.
Dr. Yao describes at paragraph 9 that the art Mirabi “discloses/observed that higher concentrations of saturated fatty acids in follicular fluid, especially palmitic and stearic acids, in some metabolic context have harmful effects on oocyte maturation” and that this supports that there is a general unpredictability in the art that teaches against the use of at least some of the claimed fatty acids.
In response, this argument is not found persuasive. Mirabi does describe that some individual fatty acids have negative effects on oocyte maturation however, Mirabi specifically teaches that higher concentrations of saturated fatty acids can have harmful effect on oocyte maturation and implantation, such effects can be counteracted by the presence of unsaturated fatty acids such as oleic acid (abstract, conclusion). Thus, Mirabi provides ample reasoning to combine the use of both a saturated fatty acid and an unsaturated fatty acid to counteract the negative effects seen and the argument is not found persuasive.
Dr. Yao describes at paragraphs 10-14 that the instant invention provides surprising and unexpected results because they found that employing albumin with reduced caprylic acid resulted in an increase in the fertilization rate as compared to an example with albumin containing caprylic acid and example of albumin in which caprylic acid had been taken out and readded. Additionally, Dr. Yao states “the present inventors surprisingly and unexpectedly discovered that the increased rate of fertilization was present even when the reduced caprylic acid containing a fatty acid utilized in Figure 4 were diluted up to 160-fold” as compared to comparative example 2 which has normal amounts of caprylic acid (i.e. no caprylic acid had been taken out).
In response, this argument is not found persuasive. The cited art provides ample evidence that the person of ordinary skill was aware of the harmful effects of caprylic acid on fertilization procedures, therefore one would assume that the experimental parameter with the lower amount of caprylic acid would have high rates of fertilization as compared to the experiments including albumin without caprylic acid removal (i.e. higher caprylic acid). None of the cited figures throughout the declaration make a comparison to experimental parameters where albumin without any caprylic acid at all provides a lower fertilization rate than albumin with low amounts of caprylic acid. Additionally, the reference to the alleged surprising and unexpected result of maintaining a high level of fertilization even when diluted 160-fold appears to be expected based on the cited art. A 160-fold dilution provides a much lower concentration of the caprylic acid and thus based on the teaching of Merkel would yield a higher fertilization rate as compared to the experiments including albumin without caprylic acid removal (i.e. higher caprylic acid). Merkel discloses that they identified octanoic acid, also known as caprylic acid can be deleterious to mammalian cell culture and particularly stem cell cultures (col 2, para 1). Merkel teaches a method of use for an albumin formulation in the culturing of gametes or of embryos for assisted reproductive technologies (such as artificial fertilization or fertilization in vitro) (col. 13, para 2), the albumin formulation having less than 0.1-0.001 mM (i.e., 100-1 micromolar) concentration of caprylic acid (also known as octanoate) (col 6, para 6). Additionally, Merkel teaches multiple human embryonic stem cell cultures which are supplemented with varying levels of octanoate (a.k.a caprylic acid), and the octanoate concentrations of 0.2/0.5/1.0 mM (conversion: 2/5/10 μmol per gram of albumin) proved to maintain the embryonic stem cell doubling times at a normal level, whereas octanoate concentrations of 8.0 mM (conversion 80 μmol per gram of albumin) did not maintain the embryonic stem cells past the second passage (Col. 42-43, Table 25). Thus, the art supports that higher concentrations of caprylic acid are known to be harmful, which aligns with results of the instant invention that a 160-fold dilution of the substance known to be harmful, caprylic acid, would result in higher fertilization rates. Thus the results are not surprising nor unexpected and the arguments are not found persuasive.
Dr. Yao describes at paragraph 13 that the art Merkel teaches away from the use of any fatty acids and cites of columns 6-7 of Merkel.
In response, this argument is not found persuasive. Merkel does not teach away from the use of these fatty acids, rather Merkel provides relatively low ranges of amounts of fatty acids in many various preferred embodiments. Merkel provides a preferred embodiment wherein many of the fatty acids are present at a concentration of 0, however a preferred embodiment does not teach away from the rest of Merkel, who teaches that fatty acids are acceptable in low concentrations. Therefore, the argument is not found persuasive.
Response to Arguments
Applicant's arguments filed 01/20/2026 have been fully considered but they are not persuasive.
Applicant argues (pg. 9-11) that each of the cited references do not teach the claimed inventions independently of the combination of the references. Applicant makes reference and provides identical arguments as the Yao Declaration addressed above.
In response to Applicant’s arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Therefore, the argument is not found persuasive.
Applicant argues (pg. 11-12) that the results obtained by the instant invention are surprising and unexpected, specifically that the results of an increase rate of fertilization is surprising and unexpected. Applicant makes reference and provides identical arguments as the Yao Declaration addressed above.
In response, this argument is not found persuasive. The cited art provides ample evidence that the person of ordinary skill was aware of the harmful effects of caprylic acid on fertilization procedures, therefore one would assume that the experimental parameter with the lower amount of caprylic acid would have high rates of fertilization as compared to the experiments including albumin without caprylic acid removal (i.e. higher caprylic acid). None of the cited figures throughout the declaration make a comparison to experimental parameters where albumin without any caprylic acid at all provides a lower fertilization rate than albumin with low amounts of caprylic acid. Additionally, the reference to the alleged surprising and unexpected result of maintaining a high level of fertilization even when diluted 160-fold appears to be expected based on the cited art. A 160-fold dilution provides a much lower concentration of the caprylic acid and thus based on the teaching of Merkel would yield a higher fertilization rate as compared to the experiments including albumin without caprylic acid removal (i.e. higher caprylic acid). Merkel discloses that they identified octanoic acid, also known as caprylic acid can be deleterious to mammalian cell culture and particularly stem cell cultures (col 2, para 1). Merkel teaches a method of use for an albumin formulation in the culturing of gametes or of embryos for assisted reproductive technologies (such as artificial fertilization or fertilization in vitro) (col. 13, para 2), the albumin formulation having less than 0.1-0.001 mM (i.e., 100-1 micromolar) concentration of caprylic acid (also known as octanoate) (col 6, para 6). Additionally, Merkel teaches multiple human embryonic stem cell cultures which are supplemented with varying levels of octanoate (a.k.a caprylic acid), and the octanoate concentrations of 0.2/0.5/1.0 mM (conversion: 2/5/10 μmol per gram of albumin) proved to maintain the embryonic stem cell doubling times at a normal level, whereas octanoate concentrations of 8.0 mM (conversion 80 μmol per gram of albumin) did not maintain the embryonic stem cells past the second passage (Col. 42-43, Table 25). Thus, the art supports that higher concentrations of caprylic acid are known to be harmful, which aligns with results of the instant invention that a 160-fold dilution of the substance known to be harmful, caprylic acid, would result in higher fertilization rates. Thus the results are not surprising nor unexpected and the arguments are not found persuasive.
Applicant argues (pg. 12) that the art Merkel teaches away from the use of any fatty acids and cites of columns 6-7 of Merkel.
In response, this argument is not found persuasive. Merkel does not teach away from the use of these fatty acids, rather Merkel provides relatively low ranges of amounts of fatty acids in many various preferred embodiments. Merkel provides a preferred embodiment wherein many of the fatty acids are present at a concentration of 0, however a preferred embodiment does not teach away from the rest of Merkel, who teaches that fatty acids are acceptable in low concentrations. Therefore, the argument is not found persuasive.
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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONSTANTINA E STAVROU whose telephone number is (571)272-9899. The examiner can normally be reached M-F 8:00-5:00.
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632
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