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 .
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.
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8, 12, 16, 23, 26-29, 32, 33, 38 and 40-50 are canceled; claims 7, 9-11, 13-15, 17-22, 24, 25, 30, 31, 34-37 and 39 are withdrawn.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.
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 04/16/2026 have been fully considered but they are not persuasive for the following reasons:
Applicant argues the claims are not obvious under 35 U.S.C. 103 (see starting at remarks page 8). Applicant summarizes previous response to remarks and the rejection, remarking that the Office Action states that the cited prior art teach that motility is a consideration in sperm selection for the most optimum selected sample, accordingly, that it would have been obvious to have performed enrichment for CD10- spermatozoid population for the purpose of improving selection for ART; Applicant remarks this is allegedly due to the relation between CD10 and motility, and motility and sample selection for ART. Applicant notes that the Office considers sperm motility as an important parameter for improved fertilization and improved pregnancy rates in IVF and ICSI (referring to Donnelly et al. and Park et al.). Applicant argues that they disagree (remarks page 10).
See at remarks page 10, Applicant refers to Annex I- Experimental Results and asserts Annex I is actual evidence demonstrating that the improved sperm motility described in the reference Subirán et al. (2010) is not dependent on CD10, that Annex I shows the percentage of CD10-positive cells in capacitated and non-capacitated spermatozoa (figure 1). It is noted that Applicant has not cited Annex I as a prior art document, and the evidence is not provided, for example as part of an affidavit/declaration. It is not clear exactly what experimental results Annex I is part of (i.e., part of the present application, additional supplementary data). Applicant is referred to MPEP 716.01(c)(II), Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Examples of statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor. Nonetheless, it is noted that Applicant remarks that Annex I explains that capacitated spermatozoa are sperm cells that have undergone physiological and biochemical changes after ejaculation, enabling them to fertilize the oocyte. Applicant argues that figure 1 demonstrates non-capacitated spermatozoa have a higher percentage of CD10-positive cells than capacitated spermatozoa, the latter showing negligible or undetectable CD10 positive cells.
In reference to this argument, this argument does not appear to be persuasive pertaining to fertility or specifically motility- specifically, non-capacitated spermatozoa are not considered to be interfertile or immotile spermatozoa, rather it appears that these spermatozoa are merely those not yet capacitated (i.e., those that have not undergone the physiological and biochemical changes that allow them to fertilize the oocyte), that such changes can be induced artificially in laboratory (e.g., using specialized media that causes activation, see for example, Rodrigo et al., What is sperm cell capacitation?-definition and the in vitro techniques. https://www.invitra.com/en/sperm-capacitation/. Last updated 02/15/2024 [Accessed: 06/03/2026]). As such, these arguments don’t appear necessarily persuasive that CD10 does not contribute to, or is related to, motility.
Applicant’s Annex I appears specific to showing CD10 expression in both capacitated and non-capacitated cells, and the Examiner acknowledges that in Annex I, Applicant reports a higher amount of CD10 positive cells in capacitated spermatozoa than non-capacitated (i.e., figure 1 demonstrates non-capacitated spermatozoa have a higher percentage of CD10-positive cells, i.e., are CD10+, than capacitated spermatozoa, the latter showing negligible or undetectable CD10 positive cells (i.e., capacitated are CD10-). Applicant further remarks (page 10) that capacitated spermatozoa with only 1% of CD10 positive sperm cells had significant increase in motility following treatment with Thiorphan (a known CD10 inhibitor) compared to control (untreated group).
This argument does not appear consistent with the cited prior art which does suggest CD10 has a role in motility, for example, Applicant’s Annex I is comparing capacitated and non-capacitated spermatozoa and not, for example, motile versus non-motile spermatotozoa. As noted above, it appears that non-capacitated can become capacitated (when appropriately conditioned), and as such it would be expected that these samples could be motile.
Additionally, in reference to Table 1, Table 1 appears to be comparing two at least somewhat motile sperm populations (i.e., effect of the inhibitor Thiophan on progressive motile sperm and highly progressive motile sperm, i.e., both are motile sperm), and not, for example, motile and non-motile.
Applicant argues that the above referenced data shown in Annex I is evidence that the mechanism for Thiorphan-induced enhancement of motility is independent of CD10 expression, thus one having ordinary skill would not have considered selection based on CD10 expression, as the prior art did not convincingly show that CD10 was an important factor for motility.
In response to this argument, as noted above, Annex I evidence has not been provided as supported by an appropriate affidavit or declaration. Further it is noted that Subirán et al., the cited prior art, shares authors in common with the claimed inventions inventors. Applicant is taking the position that this prior art did not convincingly show that CD10 was an important factor for motility. Applicant refers to the reference at 2.2 and indicates the spermatozoa in Subirán were capacitated spermatozoa, Applicant argues the improved motility observed in Subirán after treatment with Thiorphan is independent of CD10 and there is no correlation between CD10 and motility, that although thiorphan is highly selective for CD10/NEP at nanomolar concentrations, this selectivity is compromised as the dose rises, where thiorphan begins to significantly inhibit ACE.
However, referring to what was known in the prior art at the time, the reference (Subirán (2010)) does explicitly state “APN/CD13 and NEP/CD10 modulate the motility of capacitated spermatozoa, although each of the enzymes seems to participate in the control of different aspects of sperm motility”, the reference is suggesting each of these indicated enzymes as having a role in motility. It’s not clear if Annex I is additional results obtained after the publication, for example, is Applicant taking the position that since the publication was publicly available, at a later point in time it was found that CD10 was incorrectly indicated to play a role in motility.
Wang et al., A comprehensive review of the literature on CD10: its function, clinical applications, and prospects, Frontiers in Pharmacology, (2024), 15: 1336310 (13 pages), indicates that CD10 is also recognized in the art as CALLA, CMT2T, SCA43, SFE, neutral endopeptidase, and neprilysin (NEP) (see page 1, introduction paragraph). In this review article, Wang et al. report that “Several studies indicate that CD10 has considerable negative effects on sperm motility. Intriguingly, a number of studies have shown that opiorphin, found in human seminal plasma, can enhance sperm’s progressive motility. Furthermore, opiorphin has been observed to positively influence sperm motility parameters, especially in cases of male infertility marked by asthenozoospermia, leading to improved results in intrauterine insemination (Subirán et al., 2008; Pinto et al., 2010; Bosler et al., 2014; Fritz et al., 2019).”
Referring the cited prior art, Subirán (2010), relied upon in the pending grounds of rejection, and evidence such as Wang (which although is not prior art, reviews what was known previously by those in the art), it does not appear to be unreasonable to conclude from Subirán, as cited, that CD10 is related to motility, and that motility is relevant to fertility and sperm selection, and as such the reference (Subirán) is relevant to what was known in the prior art at the time. See for Example at the introduction of the prior art cited reference, “Sperm motility appears to be essential for natural reproduction and is an important and currently the most reliable predictor of male factor infertility [1, 2].”
Applicant further argues (remarks pages 12-13) that at the concentration used in Subirán (2010), both enzymes would have been inhibited, and as such one would understand the effect of thiorphan could be mediated through ACE or through CD10 inhibition. However, this is not persuasive as this argument (that those of ordinary skill reading Subirán would have concluded that it could be mediated through CD10) supports the position taken in the rejection, namely that it would have been obvious matter to try (enriching for CD10-) to obtain the optimum specimen. It is maintained, given what was known in the prior art at the time, that it would have been obvious to have enriched for CD10- cells in an effort to select motile specimen (optimize to select the best possible specimen for fertility/fertilization).
Applicant further cites Kohn et al. (1998) (referring to IDS entered prior art) as supporting that capacitated spermatozoa show immunoreactivity for ACE (remarks pages 13-15), and Shibahara et al. (2001) to support that sperm membranes express ACE, and a negative correlation with sperm motility (page 15). Applicant argues it can be appreciated that ACE is present in human capacitated spermatozoa and that it negatively correlates with motility. In response, it is not disputed that the prior art recognized ACE correlated negatively with motility; however, Subirán 2010 also supports a negative correlation with CD10.
Regarding the citation of Fernández et al. (2002), Applicant argues this reference supports that one having ordinary skill would be aware that NEP/CD10 detected in semen mainly originates from prostasomes and not from the surface of spermatozoa themselves, Applicant asserting that this confirms a person skilled in the art would not have expected negative selection of spermatozoids using CD10 binding agent would have any effect in sperm motility since CD10 detected in semen does not originate from the spermatozoa. However, this reference is well before Subirán 2010 and Subirán 2010 does state “APN/CD13 and NEP/CD10 modulate the motility of capacitated spermatozoa, although each of the enzymes seems to participate in the control of different aspects of sperm motility”, and Subirán 2010 is teaching spermatozoa isolated from semen (see end of page 899 to page 901).
For all of these reasons, Applicant’s arguments are not persuasive, and the rejections are maintained.
Conclusion
THIS ACTION IS MADE FINAL. 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.
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
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