SUPPLEMENTARY DETAILED ACTION
The present is a supplementary detailed action, which supersedes the previous action which inadvertently omitted rejections for new claims 51 and 52.
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 .
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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/21/2025 has been entered.
Priority
The present application was filed as a proper National Stage (371) entry of PCT Application No. PCT/EP2019/053615, filed 02/14/2019. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application No. 18382084.4, filed on 02/14/2019 in the European Patent Office.
Status of the Claims
Claims 1-4, 6, 7, 9-11, 13-15, 17-22, 24-25, 30, 31, 34-37, 39, 51 and 52 are pending; claims 5, 8, 12, 16, 23, 26-29, 32, 33, 38 and 40-50 are canceled; claims 7, 9-11, 13-15, 17-22, 24, 25, 30, 31, 34-37 and 39 are withdrawn. No claims are amended. Claims 1-4, 6, 51 and 52 are examined below.
Information Disclosure Statement
The information disclosure statements (IDS) filed 01/29/2025 and 01/30/2025 appear to be duplicates of IDS filed 01/22/2025 (2). The duplication references have been lined through.
The IDS filed 01/22/2025 (2) have been considered, initialed and are attached hereto.
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.
Claim(s) 1-4, 6 and 51 are rejected under 35 U.S.C. 103 as being unpatentable over Lee et al., Magnetic-activated cell sorting for sperm preparation reduces spermatozoa with apoptotic markers and improves the acrosome reaction in couples with unexplained infertility, Human Reproduction, 25(4), (2010), p.839-846 in view of Subirán et al., Control of APN/CD13 and NEP/CD10 on sperm motility, Asian Journal of Andrology, 12, (2010), p.899-902 (IDS entered 08/16/2021), Donnelly et al., In vitro fertilization and pregnancy rates: the influence of sperm motility and morphology on IVF outcome, Fertility and Sterility, 70(2), (1998), p. 305-314, and Freedman et al., WO94/08621.
Lee et al. teach MACS for sperm preparation in patients with infertility, performed in order to reduce spermatozoa with apoptotic markers (abstracts). Lee teach MACS reduced apoptotic markers. Lee teach most sperm motion characteristics were not impaired by MACS (some motility slightly decreased); Lee teach IART (induced acrosome reaction test) significantly improved (abstract). Lee conclude that spermatozoa prepared by density gradient centrifugation and then MACS results in spermatozoa with high fertilization potential (abstract), see Lee et al. teach the results of their studies suggest eliminating spermatozoa that have negative effect on fertilization (eliminating with MACS those with apoptotic markers improves outcome of fertilization potential of sperm and possibly the outcome of further ART cycles).
Although Lee teach MACS to obtain an enriched spermatozoid cell population (enriched to exclude apoptotic markers to improve motility), Lee does not teach contacting the starting population with CD10-binding agent to produce a population enriched in CD10- spermatozoids (namely isolating cells that do not bind to result in the enriched population).
Regarding the marker CD10 and spermatozoa, Subirán et al. teach the marker CD10 (NEP/CD10) recognized as an enzyme present in sperm cells involved in regulation with motility (abstract), Subirán’s results show inhibition of CD10 as related to improved motility (the reference suggesting CD10 negatively impacts motility).
Donnelly et al. investigated the influence of sperm motility and morphology on IVF outcome, see specifically at the conclusion of the abstract, Donnelly teach that both sperm motility parameters and precent normal morphology are significant factors in predicting fertilization and pregnancy rates in IVF (see also page 309, col. 1, para 3, significant correlation between progressive motility and fertilization, para 4, significant positive correlation between progressive motility and pregnancy rates). At page 310, end of Col. 2, Discussion to page 311, Donnelly teach sperm motility is believed to be one of the most important parameters in evaluating the fertilizing ability of ejaculated sperm, and fertilization rates of human oocytes in vitro have been shown to correlate closely with sperm motility.
Freedman et al. teach antibody coated magnetic particles, including anti-CD10 magnetic particles (see for example Freedman at claims 1-4).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to have modified the MACS method of Lee, to further contact the cell population with the anti-CD10 coated magnetic particles of Freedman et al., thereby producing CD10- spermatozoid population, in order to deplete a population of cells expressing this marker, one motivated to do so because the prior art showed that CD10 (enzyme present in sperm cells, involved in regulation with motility) negatively impacts mobility (Subirán) and because the prior art (e.g., Donnelly et al.) suggests that motility is a factor to be considered, specifically that there is a significant positive correlation between motility and pregnancy rates.
One would have been motivated to further deplete the population of at least CD10 expressing spermatozoa, to produce a population with greater fertilization potential (the goal in Lee), by selecting the optimal sperm to maximize potential ART success (Donnelly, for example regarding the ART IVF, teaching motility as a significant consideration, thereby also addressing claim 51).
Additionally, although Subirán et al. considered inhibition of CD10 rather than screening for CD10- populations, the modification to screen for CD10- cells would have been an obvious matter try as a result of the finding of Subirán et al. which suggest the presence of CD10 on spermatozoa has a negative effect on motility. This knowledge, combined with the teaching of Donnelly motivates one having ordinary skill in the art to modify Lee in order to enrich for CD10- spermatozoids for the purpose of improving selection for ART, as an obvious matter to try to obtain the optimum specimen. Specifically, the prior art before the effective filing date of the claimed invention recognized that CD10 negatively impacted motility (based on the CD10 inhibition studies of Subirán ), further the prior art teaches motility as a consideration in sperm selection for ART. Based on this knowledge available in the prior art, it would have been predictable that those cells negative of CD10 would have improved motility and as a result would be optimal (as compared to those positive for CD10) for ART.
One having ordinary skill in the art would have a reasonable expectation of success, further modifying the MACS technique as indicated above to deplete spermatozoa expressing CD10 because this would align with Lee’s goal, to improve fertilization, and further because such magnetic particle reagents, comprising antibody to CD10, were already known and available to those having ordinary skill in the art (Freedman).
Regarding claim 2, see above, the combination of the cited art teaches anti-CD10 antibody as the binding agent.
Regarding claim 3, see above, the combination of the cited art teaches isolation by MACS (magnetic-activated cell sorting).
Regarding claims 4 and 6, Lee et al. teach methods performed on human subject’s experience infertility.
Claim(s) 52 is rejected under 35 U.S.C. 103 as being unpatentable over Lee et al., in view of Subirán et al., Donnelly et al., and Freedman et al., as applied to claim 1 above, and further in view of Park et al., Influence of motility on the outcome of in vitro fertilization/intracytoplasmic sperm injection with fresh vs. frozen testicular sperm from men with obstructive azoospermia, Fertility and Sterility, 80(3), (2003), p. 526-530.
The combination of the cited art addresses the method substantially as claimed, the combination addressing ART such as in vitro IVF (see Donnelly et al.).
However, the combination of the cited art is not teaching ART that is ICSI (claim 52).
Park et al. assessed the efficacy of fresh versus frozen sperm on fertilization and pregnancy using ICSI, see at page 527, Park indicate the purpose was to assess the influence of motility of fresh versus frozen specimens. At page 528, Park report that no differences in fertilization and pregnancy rates were observed using fresh or thawed sperm, Park teaching the presence of sperm motility provided for optimal fertilization and pregnancy results. Park reported that by characterizing sperm motility after thawing, they have shown tht the quality of sperm motility is adequate for ICSI for most men, Park teaching in cases of absence of motile sperm after thawing, selection was based on normal morphology (thereby suggesting motility is a first consideration in terms of selection for best outcomes). Park indicate their results suggest that successful pregnancy in TESE-ICSI treatment is influenced by motility (see page 529, last paragraph to page 530, first paragraph).
It would have been further prima facie obvious to one having ordinary skill in the art to have modified the combination of the cited art to substitute the ART ICSI for IVF, as taught by Donnelly et al., namely, to have applied the method as taught by the cited prior art (to further deplete the population of at least CD10 expressing spermatozoa, to produce a population with greater fertilization potential (i.e., the goal in Lee), by selecting the optimal sperm to maximize potential ART success (Park et al.), to have used the spermatozoids isolated as indicated by the combination of the prior art for ICSI (in place of IVF) because like with IVF motility is indicated to be an important consideration of ICSI (Park et al.), both IVF and ICSI are art recognized and applied ART techniques known to those of ordinary skill in the art.
The modification to use ICSI in place of IVF would have been a simple substation of one assisted reproduction technique for another, both recognized for the purpose of achieving pregnancy and both of which consider motility as a factor for consideration for success. One having ordinary skill would have a reasonable expectation of success using ICSI in place of ART such as IVF considering both are art recognized assisted reproduction techniques, and considering that the prior art supports motility as an important factor to consider for success in either (i.e., ICSI would be expected to also benefit from a depletion method that results in selection of those sperm considered most motile).
Response to Arguments
Applicant's arguments filed 01/21/2025 have been fully considered but they are not persuasive for the following reasons.
Regarding the rejection of claims under 35 U.S.C. 103, Applicant refers to the amendments to the claims in order to overcome the previous grounds of rejection (see remarks page 9). Applicant argues the claims as amended recites the purpose of the spermatozoid cell population enriched in CD10- spermatozoids is for using the enriched sample in assisted reproduction technique (ART). Applicant argues that Subirán et al. does not suggest that CD10 could be used for selection in ART procedures, that there is no motivation to use CD10- spermatozoids in ART.
However, see amended grounds of rejection as set forth in detail above, for the reasons of record indicated in the rejection above, one having ordinary skill, based on the knowledge provided by the prior art, would have been motivated to perform enrichment for CD10- for the purpose of improving selection for ART (see as discussed above, the art supporting a relation between CD10 and motility, and motility and sample selection for ART).
Regarding previous remarks to Applicant’s argument referenced from page 8 of the Final Action 07/22/2025 (Applicant’s present remarks at page 10, referring to previous response to previous remarks), Applicant argues Subirán is limited to showing that inhibition of CD10 enzymatic activity leads to improvement of sperm motility, and thus, there is a negative relationship between the enzymatic inhibition of CD10 and sperm motility. Applicant asserts that Subirán et al. is exclusively focused on studying the behavior of CD10- expressing spermatozoids in which CD10 has been inhibited, but does not explain the effect on sperm motility in those that do not express CD10 at all. Applicant argues that the effect on sperm motility resulting from inhibition of CD10 enzymatic activity disclosed in Subirán does not necessarily imply that an improved sperm motility will be observed after selecting a spermatozoid population based on the absence of CD10 expression.
Regarding Applicant’s remarks, see amended grounds of rejection set forth in detail above, the claimed invention is determined to be obvious over the prior art as set forth above. In response to Applicant’s remarks, although Subirán is directed at investigating CD10 inhibition, nonetheless the reference still suggests the correlation between the enzyme and motility. Given what is known to one having ordinary skill in the prior art, namely the suggestion that CD10 has a negative impact on motility, and further that motility is a factor to consider in selection for ART such as IVF (e.g., see Donnelly), it would have been obvious (as an obvious matter to try) to have further enriched the sample in terms of motility. Considering that inhibition of CD10 improves motility, one having ordinary skill would reasonably expect its absence would also similarly improve motility.
Regarding remarks at page 11, Applicant argues that even if for the sake of argument that one having ordinary skill would consider selection based on absence of CD10, it would nonetheless still not be obvious how to use this CD10- spermatozoid population. Applicant refers to Sakkas et al. as disclosing that ART is not very effective despite decades of research, Applicant citing Sakkas as teaching motility is not a relevant parameter (referring to page 715, left col. , section “Assisted reproduction and sperm selection” and section “What are we missing and is sperm selection important?”). Applicant further remarks that Sakkas discloses there are differences in fertilization rate even when a reasonable number of motile spermatozoids are present, Applicant arguing that Sakkas is suggesting that the selection based on motility is not an adequate criteria in ART (remarks page 12, referring to page 715, left column).
However, Applicant’s argument and citation of Sakkas et al. is not persuasive, Sakkas does not clearly discourage, disparage or discredit motility as a consideration in sperm selection for ART procedures. For example, this reference does not teach away from considering mobility during selection. Regarding Sakkas at page 715, left column, the question advanced in Sakkas “are all motile sperm capable of fertilization or it is a purely random event” as well as “why are the overwhelming majority of motile cells in subfertile men incapable of fertilizing an egg in vitro”, these citations from Sakkas are not tantamount with suggesting or stating that motility is not a consideration in selection for procedures such as ART, further these citations do not dispute that considering motility would improve selection. While motility is not a singular and only factor to predict an optimum specimen for ART, it does appear to be a relevant, significant consideration based on the prior art (Donnelly and Park).
See for example, this position is support by the prior art cited in the rejection above, namely Donnelly et al., which specifically states that motility parameters and precent normal morphology are significant factors in predicting fertilization and pregnancy rates in IVF, and also Park et al., which supports more motile sperm are associated with higher expectation of successful pregnancy.
Other evidence (not relied upon in the rejection, but which supports the Office’s position that motility is a consideration when selecting samples for ART), include for example Zamir et al., WO95/01799, teaching in IVF (a specific form of ART), improvement in motility properties of the spermatozoa is one mechanism for facilitating fertilization (among others such as attracting the spermatozoa to the oocyte, and enhancing acrosome reaction after capacitation). Zamir is further evidence that supports (improved) motility is just one consideration when it comes to fertilization.
See further, more recently published is Cherouveim et al., Artificial intelligence for sperm selection- a systemic review, Fertility and Sterility, 120(1), (2023), pages 1-24 (not prior art); Cherouveim is more recently published evidence that supports that motility is an important consideration in selection of sperm for ART. Cherouveim teaches regarding WHO guidance regarding sperm selection, that in addition to morphology, motility is also assessed during the process of sperm selection for fertilization (see page 24, col. 3, second paragraph, “motility is also assessed visually by the embryologist”). See further page 28, end of col. 1 to col. 2, Cherouveim teach sperm motility is an important semen parameter because it describes sperm ability to travel toward the oocyte during natural fertilization, see the reference teaches embryologists use motility to assess male fertility, select optimal sperm, as defined by the WHO, and maximize potential ART success, particularly in IVF and ICSI.
See also as supportive evidence of Examiner’s arguments, Jeyendran et al., Selecting the most competent sperm for assisted reproductive technologies, 111(5), (2019), 13 pages (also not prior art, however is art that supports the position that motility is an important consideration in selection for ART). Jeyendran et al. teach that goal of sperm selection is isolating the competent (high quality) sperm (see page 851, col. 3 to page 852 first column, first paragraph). Jeyendran et al., while acknowledging that not all motile sperm are fertile (page 852, col. 2, para 3), does teach (page 852, col. 1, last paragraph) that retrieval of motile sperm is generally considered to be essential to the success of ART. This evidence further supports the position taken by the Examiner in the present response to arguments that while motility is not the only factor to consider for fertility by ART, it is still an important consideration.
Based on both the cited prior art, and the more recent evidence published in the art, it appears that motility has long been considered an important factor in the selection of spermatozoa for ART.
Applicant further refers to the Declaration provided by Dr. José Roberto Matorras Weinig, PhD, MD, submitted under 37 CFR 1.132 on 01/21/2025 (herein after referred to as the Weinig Declaration). Applicant argues the Weinig Declaration is evidence that even if a person of ordinary skill in the art, in view of Subirán et al. 2010, would consider depleting spermatozoids expressing at least CD10 to obtain a population with improved sperm motility, this effect would not be obvious to obtain a successful fertility rate in ART because Applicant’s arguments and the Weinig Declaration assert that motility is not a relevant criteria to select a spermatozoid population to be used in ART (see the Weinig Declaration at paragraphs 5 and 6). Specifically at paragraph 6 of the Weinig Declaration, it is asserted that “sperm motility was not necessary to be used when selecting those sperm samples which had a higher probability of leading to a successful pregnancy”.
The arguments and the Weinig Declaration are fully considered. However, these arguments are not persuasive particularly in view of the reference cited at the amended grounds of rejection (namely Donnelly et al.), as well as the additionally cited supportive evidence at the response to arguments discussed above. The prior art does support that motility is a consideration in sperm selection for the most optimum selected sample. As such, while motility does not necessarily confer fertility, based on the prior art of record, as well as the state of the prior art at the time (referring to evidence in response to arguments) there is motivation to also screen and select for motility, as this (as well as other considerations) contributes to an expectation of success with ART.
Further, the Weinig Declaration supports the position taken by the office that while not the only factor, motility is a consideration when performing ART. See for example the Weinig Declaration at para 6, states “In fact, the most common technique for sperm selection in IUI and FIV treatments, including and recommended by WHO (WHO laboratory manual for the examination and processing of human semen, 2010), is the density gradient sperm separation, which is rely on a forced centrifugation passage through a differential gradient to select better quality spermatozoa that includes not only motility but also other parameters such as morphology…”.
In response to Applicant’s arguments, it is not disputed that there are many factors and considerations that go into selection of sperm for ART, however among those considerations, motility is clearly one of them. There is motivation in the prior art (as set forth in the prior art rejection in detail above under 35 U.S.C. 103), supporting that one having ordinary skill would be motivated to also enrich a specimen for motility, as based on the art.
For all of these reasons, Applicant’s arguments are not persuasive, and the claims are rejected as indicated in detail above.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELLEN J MARCSISIN whose telephone number is (571)272-6001. The examiner can normally be reached M-F 8:00am-4:30pm.
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/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677