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
The preliminary amendment filed 03/08/2023 is acknowledged. Claims 2, 4-6, 8, 9, 11-17 are amended and claims 18-20 are new. Claims 1-20 are under examination.
Effective Filing Date
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 365(c) and foreign priority are acknowledged. Under the AIA , the effective filing date of a claimed invention is the earlier of:
The actual filing date of the application;
OR
The filing date to which the application is entitled to a right of foreign priority or domestic benefit as to such claimed invention.
Based on the information given by Applicant and an inspection of the application, the examiner has concluded that the subject matter defined in the instant claims is supported by the disclosure in PCT/EP2021/075820 because the claimed invention is disclosed in said application.
Note that with regard to claiming foreign priority, the foreign priority date is the effective filing date of the claimed invention IF
the foreign application supports the claimed invention under 112(a), AND
the applicant has perfected the right of priority by providing:
a certified copy of the priority application, and
a translation of the priority application (if not in English).
In the instant case, the certified copy of the foreign priority application is in English and supports the claimed invention under 112(a), therefore, the effective filing date of the instant application is 09/18/2020.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: EVALUATING SPERM HEALTH COMPRISING MEASURING MEMBRANE-BOUND RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS (mRAGE).
Claim Interpretation
Claim 1, step (c) recites “evaluating sperm health based on the quantitative or qualitative level of the biomarker”. Since “level” refers to a quantity or amount, the use of the definite article (“the”) is not indefinite in this context. Dependent claims 2, 4-8, 12 and 18 recite “quantifiable levels”, which is interpreted as synonymous with “quantitative level”.
Claim 14 recites that the evaluating sperm health step further comprises “processing the sample using separation techniques”, including density gradient centrifugation (DGC) and the swim-up method, and claim 15 recites that these methods result in an at least a 2-fold decrease in mRAGE positive sperm compared to mRAGE negative sperm; and/or an at least a 2-fold increase in PR sperm, and/or a 2-fold decrease in cell permeability, and/or an at least a 2-fold decrease in apoptotic sperm, which indicate sperm that can be used in assisted reproductive technologies (ART). According to Bibi et al. (Biomedicines 2023, 11, 467), separation techniques such as DGC and swim-up are methods used during ART to enhance sperm quality by separating healthy, motile sperm from poor quality sperm. Claims 14 and 15 ultimately depend from claim 1, and are interpreted as being carried out on all patients, both those with mRAGE positive and mRAGE negative sperm. In addition, claim 14 recites “any one or more of…the sperm swim-up method”. Since the swim-up method is a known method of processing sperm, the use of the definite article is not ambiguous in this context because it would be reasonably ascertainable by those skilled in the art what method is being referred to.
Claim 19, which depends from claim 15, recites “if the sperm of the patient are determined to be useful in the ART procedure, using the sperm of the patient to conduct the ART procedure, indicates that performing ART is conditional.
Claim Objections
Claims 1, 4-9, 12, 13 and 18 are objected to because of the following informalities.
(i) Claim 1 recites the quantitative level while dependent claims 2, 4-8, 12 and 18 recite “quantifiable levels”. The phrases “quantitative level” and “quantifiable levels” are redundant since the term “level” already indicates an amount or quantity. For the sake of parallel structure, it is also suggested that claims 1, 2, 4-8, 12 and 18 be amended to recite simply “level” or “levels” so that a single phrase should be used throughout the claims.
(ii) The acronyms IM, NP and PR should be defined as they are at p. 9, lines 17-19 of the instant specification. For instance, the claim portion should recite “immotile (IM), non-progressively motile (NP) or progressively motile (PR)”.
(iii) Claim 13 recites “wherein there is at least a 2-fold decrease in cell permeability in mRAGE positive sperm compared to mRAGE negative sperm is indicative of poor sperm health” in lines 3-4 and “wherein there is at least a 2-fold increase in apoptosis and necrosis in mRAGE positive sperm compared to mRAGE negative sperm is indicative of poor sperm health” in lines 6-7. These wherein clauses are grammatically awkward. It is suggested the claim be amended to insert a comma (,) followed by “which” after “sperm”, as is done in lines 10-11 of the claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “qualitative level” in lines 4 and 5 of the claim, a term which is not defined in the instant specification. The plain meaning of the word “qualitative” is a characteristic or nature of something, rather than its quantity or number, therefore the pairing with the term “level”, which means an amount or quantity, is unclear.
Claims 6 and 7 recite the quantifiable levels of the biomarker (mRAGE) may deviate by “at least 1-fold” when evaluating the patient’s sperm health. However, a 1-fold change, for instance, x/x = 1, means no change. The claim is unclear because there is one embodiment in which the sperm health is evaluated by observing no change.
Claim 11 recites “substantially oval in shape”. The term “substantially” is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. According to Pelzman (Reprod Med Biol. 2024; 23:e12594), normal sperm appearance is defined by the WHO 6th edition guidelines: classification of sperm morphology as smooth, regular contour and oval shape (see p. 2, Table 1). Thus, while the term, “regular” has a clear unambiguous meaning in the art, the term “substantially” does not. Further, Figure 1 of Pelzman shows a number of substantially oval sperm heads that nevertheless have abnormal morphology.
Claim 14 recites that the evaluating sperm health step further comprises “processing the sample using separation techniques, including any one or more of density gradient centrifugation (DGC) and the sperm swim-up method.” In the context of this claim “including” is interpreted as open language, like “comprising” (see MPEP 2111.03(I)). The list following “any one or more of” appears to be a Markush grouping, which is a claim element defined by selection from a group of alternatives (see MPEP 2117 and 2173.05(h)). A Markush group requires selection from a closed group “consisting of”, rather than “comprising” or “including” the alternative members (see MPEP 2111.03(II), citing Abbott Labs. v. Baxter Pharmaceutical Products Inc., 334 F.3d 1274, 1280, 67 USPQ2d 1191, 1196-97 (Fed. Cir. 2003)). See MPEP 2173.05(h):
If a Markush grouping requires a material selected from an open list of alternatives…the claim should generally be rejected under 35 U.S.C. 112(b) as indefinite because it is unclear what other alternatives are intended to be encompassed by the claim. See In re Kiely, 2022 USPQ2d 532 at 2* (Fed. Cir. 2022).
If the claim element is intended to encompass combinations or mixtures of the alternatives set forth in the Markush grouping, the claim may include qualifying language preceding the recited alternatives (such as “at least one member selected from the group consisting of”), or within the list of alternatives (such as “or mixtures thereof”).
Claims 2-5, 8-10, 12, 13 and 15-20 are also included in this rejection for depending upon an indefinite claim without resolving the indefiniteness.
Claim Rejections - 35 USC § 101
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 1-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more. The claims recite an in vitro method of evaluating sperm health comprising providing a biological sample from a patient, measuring the quantitative or qualitative level of a biomarker in the sample; and evaluating sperm health based on the quantitative or qualitative level of the biomarker, wherein the biomarker is membrane-bound receptor for advanced glycation end products (mRAGE). Thus, the claims are drawn to the statutory category of a process. See Step 1 of the Revised Guidelines.
The first step in determining whether a claim recites patent eligible subject matter is to consider whether the claims recite an abstract idea, law of nature or a natural phenomenon. See Prong One of Step 2A in the Revised Guidelines. As noted above, the claims are drawn to a method of evaluating mRAGE in sperm in order to evaluate sperm health and diagnose infertility (see claim 17). Dependent claim 16 defines the patient population as any one or more of non-diabetic, non-smoking and non-obese. Dependent claims 2-15 and 18-20 further define the evaluating step(s) and are grouped in the table below by dependency:
Claim(s)
Evaluating Step(s)
2-4
Absence of mRAGE on sperm cells defines the patient as mRAGE negative (normal or sperm health) and presence of mRAGE on sperm cells defines the patient as mRAGE positive (poor sperm health, motility abnormal sperm or infertility).
5-7
Comparing the amount of sperm expressing quantifiable levels of mRAGE to the amount of sperm not expressing quantifiable levels of mRAGE and claims 6 and 7 recite a 1-fold deviation defines mRAGE positive and negative samples.
8
A 10-fold deviation in Mean Fluorescent Intensity (MFI) value of the sperm expressing mRAGE from mRAGE negative sperm defines the patient as mRAGE positive; and/or a 10-fold deviation in MFI value of the sperm not expressing mRAGE from mRAGE positive sperm defines the patient as mRAGE negative.
9-10
A further step of assessing sperm motility as (1) immotile (IM—poor sperm health) or (2) non-progressively motile (NP) or progressively motile (PR—normal sperm health) and claim 10 recites the amount of mRAGE positive sperm is inversely correlated to the amount of PR sperm.
11
A further step of assessing sperm morphology.
12
A further step of assessing mitochondrial membrane potential (MMP), wherein MMP indicates of mRAGE negative sperm and the absence of MMP indicates mRAGE positive sperm.
13
Further steps further of assessing cell permeability, apoptosis and necrosis, and/or DNA fragmentation.
14-15; 19-20
Further step of processing the sample using separation techniques including density gradient centrifugation (DGC) and the swim-up method; claim 15 recites these techniques result in sperm improvement; claim 19 recites determining whether the sperm processed by this method results in sperm capable of use in an assisted reproduction technologies (ART) procedure and claim 20 recites types of ART.
18
Treating the patient for infertility if the evaluating steps indicate the patient is mRAGE positive.
Thus, the claims recite the mental steps of evaluating, comparing and assessing. The judicial exception is based upon the correlation between mRAGE expression in sperm (along with sperm motility, sperm morphology, cell permeability, apoptosis/necrosis, and DNA fragmentation) and male infertility. The mental step of comparing biomarker levels is similar to comparing information regarding a sample or test subject to a control or target data (see Univ. of Utah Research Found, v. Ambry Genetics Corp., 113 USPQ2d 1241 (Fed. Cir. 2014), or diagnosing an abnormal condition by performing clinical tests and thinking about the results (see In re Grams, 12 USPQ2d 1824 (Fed. Cir. 1989). The answer to Prong One of Step 2A is yes.
The second step in determining patent-eligibility of claimed subject matter is to consider whether the claims recite additional elements that integrate the judicial exception into a practical application. The claims require providing a sample and performing measurements (mRAGE) and assessments (sperm motility, sperm morphology, cell permeability, apoptosis/necrosis, and DNA fragmentation), however, sample collection, mRAGE measurement and sperm assessments are merely the necessary data gathering steps required in order to perform the mental analysis of comparison and diagnosis. Claims 14 and 15 require sperm separation, which can be a treatment, but in the context of the claims, including dependent claims 19 and 20, it is carried out for the purpose of evaluating whether the sperm is suitable for use in ART, and therefore, is another method of data gathering in order to perform diagnosis. Claim 18 recites “treating the patient for infertility” however, this treatment is not particular; rather it constitutes mere instructions to “apply” the exception in a generic way. Thus, the administration step does not integrate the mental analysis step into a practical application. Further, even if claim 18 recited a particular treatment, the treatment step is conditional; namely, the patient is treated if he is defined as mRAGE positive. The answer to Prong Two of Step 2A is no.
The final step in determining subject matter eligibility is to consider whether
the claims recite additional elements that are sufficient to amount to significantly more than the judicial exception. The claims do not recite any particular methods of measuring the quantitative or qualitative level of a biomarker. The specification discloses quantitative assessment of RAGE protein expression with a commercially available mouse-anti-human RAGE antibody and analysis of sperm health using commercially available flow cytometry materials (see p. 31, lines 10-14 and lines 30-38). Claim 8 recites using the Mean Fluorescent Intensity (MFI) value to evaluate sperm health, but using MFI in flow cytometry is routine in the art. See Skibinska et al. (Asian Journal of Andrology (2018) 20, 425-431), who teach using flow cytometry analysis to measure the expression of another protein (PELP1) “in human spermatozoa from normal and abnormal semen samples” (see p. 428, right column, 3rd paragraph; p. 429, Figure 5; also, Supplementary Table 2). Further, the treatment recited in claim 18 is a non-specific treatment that is conditionally administered. The additional steps are simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality to the judicial exception (see MPEP 2106.05(d)).
Thus, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Notice for all US Patent Applications filed on or after March 16, 2013: 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.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 1-7, 9-11, 16 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Mallidis et al. (Human Reproduction, 2007; 22: 2169-2177—on IDS filed 03/09/2023). The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. Mallidis et al. teach evaluating sperm health comprising obtaining a sperm sample from patients (see p. 2170, right column, 3rd paragraph; p. 2174, Figure 5, which depicts quantification of RAGE protein in sperm). Further, Mallidis et al. teach immunocytochemical localization of RAGE on sperm (see 2173, Figure 2, depicting localization mostly in the nucleus and head regions; also, p. 2174, Figures 4-5). Mallidis et al. teach that “semi-quantitative analysis of the immunostaining of sperm from diabetic and non-diabetic men (Fig. 3a) found that the majority of sperm (>60%) in samples from diabetic men…showed the presence of RAGE, a proportion approximately three times greater than that seen in samples from non-diabetic men” (p. 2173, left column, last paragraph). Mallidis et al. teach assessing sperm motility according to WHO recommendations and morphology according to Tygerberg Strict Criteria (see p. 2170, right column 3rd paragraph; see p. 2171, Table 1). Mallidis et al. teach that of the subjects (n=21), only two were smokers (see p. 2170, right column, 2nd paragraph under “Subjects”).
Mallidis et al. report that RAGE is expressed in both non-diabetic and diabetic patients in their study, however, given that the controls were drawn from a pool of men undergoing infertility investigations (see p. 2170, right column, 2nd paragraph), it flows therefrom that all of the patients were mRAGE positive. It is noted that claims 6 and 7 recite a 1-fold difference defines a patient as either mRAGE negative or positive, however, a 1-fold difference is equivalent to no difference. Nevertheless, the study showed that diabetic men had a 3-fold increase in RAGE expression vs. non-diabetic men. In summary, the teachings of Mallidis et al. meet limitations set forth in claims 1-7, namely, an in vitro method of evaluating sperm health comprising collecting a sample measuring RAGE levels and evaluating sperm health based on said measurements. Since Mallidis et al. teach assessing sperm motility and morphology, it flows therefrom that they meet limitations set forth in instant claims 9 and 11. Further, since Mallidis et al. teach that only 2 of a total of 21 subjects were smokers, the other 19 subjects were non-smokers and therefore meet the limitations of claim 16.
Finally, claim 10 recites the amount of mRAGE positive sperm is inversely correlated to the amount of progressively motile (PR) sperm represents an innate characteristic of mRAGE expression; namely, the more mRAGE positive sperm, the fewer PR sperm, and vice versa. Mallidis et al. teach that RAGE expression expands in pathological states. See p. 2170, left column, 4th and 5th paragraphs:
AGEs are capable of damaging DNA either directly or by the generation of ROS via the activation of the receptor for AGEs (RAGE). RAGE is a member of the IgG superfamily and is a multiligand receptor with a high affinity for, amongst others, several AGE-modified proteins (e.g. β-amyloid, amphoterin and S 100/calgranulins). AGE binding to RAGE in many cell types provokes a range of pathophysiological responses linked to the downstream activation of NFκB and other signaling pathways that lead to ROS generation and certain pro-inflammatory responses. Suppression of RAGE-ligand binding using soluble RAGE or neutralizing antibodies has been shown to prevent various pathological events in a range of cells. (Citations omitted by examiner).
The person having ordinary skill in the art would have recognized that RAGE levels are increased in pathological states. Further, the subjects described in Mallidis et al., expressing increased RAGE levels in sperm, would inherently have correspondingly decreased numbers of PR sperm since this was known to be a natural correlation that exists in the body. Further, for the record, the express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 102 or 103. “The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness.” In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995) (affirmed a 35 U.S.C. 103 rejection based in part on inherent disclosure in one of the references). See also In re Grasselli, 713 F.2d 731, 739, 218 USPQ 769, 775 (Fed. Cir. 1983). See also MPEP 2112.
The second factor to consider is to ascertain the differences between the prior art and the instant claims. Mallidis et al. do not explicitly teach quantifying membrane bound RAGE (mRAGE). In addition, Mallidis et al. are conducting a scientific study and do not specifically teach diagnosing infertility. These issues are considered in turn.
Regarding mRAGE, Mallidis et al. teach “[l]evels of all forms of RAGE were measured using the DuoSet® ELISA system (R & D Systems, Oxon, UK—see p. 2171, left column, 3rd paragraph). Thus, although the Mallidis et al. do not explicitly disclose measuring “membrane-bound”, they do teach that “all forms of RAGE were measured” (emphasis added). Further, in the RAGE localization experiments, Mallidis et al. report:
[I]t is the specificity of RAGE expression on the acrosomal cap and the equatorial region of the sperm head, regardless of the diabetic status of the man, i.e. particularly noteworthy. This precisely mirrors the specificity of distribution of CML [Nε-carboxymethyl-lysine—a form of AGE] on sperm that we previously reported. It is this area, the acrosomal region, that undergoes a number of modifications during epididymal maturation. It constitutes a direct access point to the underlying nDNA and may also be the site of potentially the greatest RAGE induced damage. (Citations omitted by examiner).
The presence of RAGE on the outer area of the sperm (head and acrosomal cap) suggests a membranal localization.
Regarding infertility diagnosis, Mallidis et al. conclude the presence of RAGE may play a central role in sperm DNA damage. See p. 2176, left column, last paragraph:
The role of RAGE and its numerous ligands in diverse processes such as tissue damage, cell death, inflammatory response, oxidative stress and DNA fragmentation in various organs and cells, suggests that the presence of RAGE in the male reproductive tract may be a portent of its involvement in a multitude of similar but, as yet, unexplained conditions which ultimately result in male infertility.
It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to modify the teachings of Mallidis et al. by using RAGE measurements as part of diagnosing infertility because they suggest that its role in oxidative stress and DNA fragmentation may lead to idiopathic infertility in males (see above citation). The person of ordinary skill in the art would have been motivated to do so because Mallidis et al. teach that male fertility is declining, even among the young, “particularly decreased sperm counts and quality”, but there is little information about the origins of unexplained male infertility (see paragraphs bridging the left and right columns of p. 2169). Furthermore, the person of ordinary skill in the art could have reasonably expected success because Mallidis et al. teach were able to clearly distinguish differing levels of RAGE among a population of men undergoing infertility screening.
Thus, the claims do not contribute anything non-obvious over the prior art.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Mallidis et al. as applied to claims 1-7, 9-11, 16 and 17 above, and further in view of Skinbinska et al. (Asian Journal of Andrology (2018) 20, 425-431). The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. The teachings of Mallidis and colleagues and how they meet the limitations of claims 1-7, 9-11, 16 and 17 are outlined above in the preceding rejection and are hereby incorporated. The second factor to consider is to ascertain the differences between the prior art and the instant claims. Mallidis et al. do not teach evaluating sperm by evaluating a 10-fold difference in Mean Fluorescent Intensity (MFI) of mRAGE levels.
Skibinska et al. teach using flow cytometry analysis to measure the expression of another protein (PELP1) “in human spermatozoa from normal and abnormal semen samples” (see p. 428, right column, 3rd paragraph; p. 429, Figure 5; also, Supplementary Table 2). It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to modify the teachings of Mallidis et al. by using flow cytometry to measure mRAGE in semen because Mallidis shows that diabetic men expressed three times the levels of RAGE vs. control men undergoing infertility investigations. One having ordinary skill in the art would expect that flow cytometry, a well-established technique for visualizing differing protein levels, could be used to show dramatic differences, such as 10-fold, in RAGE levels between healthy and unhealthy sperm populations because it already showed a three-fold RAGE difference between diabetic and non-diabetic subfertile men. The person of ordinary skill in the art would have been motivated to use flow cytometry and MFI because it allows for quantitative visual analysis of protein levels (see Skibinska et al., p. 429, left column, 1st paragraph). Furthermore, the person of ordinary skill in the art could have reasonably expected success because of the ease of visualization of various parameters using the flow cytometry and MFI (see p. 429, Figure 5; also, Supplementary Table 2).
Thus, the claims do not contribute anything non-obvious over the prior art.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Mallidis et al. as applied to claims 1-7, 9-11, 16 and 17 above, and further in view of Paoli et al. (Fertility and Sterility, 2011; 95: 2315-2319). The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. The teachings of Mallidis et al. and how they meet the limitations of claims 1-7, 9-11, 16 and 17 are outlined above in a preceding rejection and are hereby incorporated. The second factor to consider is to ascertain the differences between the prior art and the instant claims. Mallidis et al. do not teach using mitochondrial membrane potential (MMP or Δψ) to further assess sperm health.
Paoli et al. teach that a positive correlation between MMP and sperm motility, “suggesting that sperm motility may be dependent on the functional integrity of the mitochondria” and that there is a correlation between reduced MMP and reduced sperm motility and fertility (see abstract; p. 2315, right column; p. 2319, right column, last paragraph). It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the teachings of Mallidis et al. by evaluating sperm using MMP, as taught in Paoli et al. because Paoli et al. demonstrate that MMP is not merely a qualitative measure, but “a quantitative function of motility” (see p. 2319, bottom of left column). The person of ordinary skill in the art would have been motivated to evaluate MMP because Paoli et al. report reduced MMP is associated with impaired/reduced sperm motility and male infertility (see p. 2315, right column; p. 2317, left column, 1st paragraph). Furthermore, the person of ordinary skill in the art could have reasonably expected success because of the Paoli et al. show a clear correlation between lack of motility and “extremely low MMP” (see p. 2318, let column).
Thus, the claims do not contribute anything non-obvious over the prior art.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Mallidis et al. as applied to claims 1-7, 9-11, 16 and 17 above, and further in view of Karimi et al. (Andrologia 2012, 44, 280-286—on IDS filed 03/09/2023). The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. The teachings of Mallidis et al. and how they meet the limitations of claims 1-7, 9-11, 16 and 17 are outlined above in a preceding rejection and are hereby incorporated. The second factor to consider is to ascertain the differences between the prior art and the instant claims. Mallidis et al. do not teach evaluating sperm health by assessing DNA fragmentation, wherein there is at least a 2-fold increase in DNA fragmentation in mRAGE positive sperm compared to mRAGE negative sperm, and indicative of poor sperm health.
Karimi et al. teach that in a population of diabetic men, RAGE protein levels and DNA fragmentation was significantly higher in sperm (see abstract; p. 284, Figure 4). It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to modify the teachings of Mallidis et al. by measuring DNA fragmentation when evaluating sperm health, as taught in Karimi et al. because Karimi et al. teach there is a linear association between the amount of RAGE expressed in sperm and the levels of DNA fragmentation (see p. 284, Figure 4 and right column, 2nd paragraph). The person of ordinary skill in the art would have been motivated because relying upon conventional sperm parameters alone are not enough to evaluate sperm health or male infertility (see p. 284, left column, 2nd paragraph of Karimi and colleagues). Furthermore, the person of ordinary skill in the art could have reasonably expected success because Karimi et al. report that their study links RAGE levels and DNA fragmentation in sperm, which may further reveal a mechanism of action of unexplained male infertility in diabetics (see p. 284, left column, last paragraph).
Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 14 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Mallidis et al. as applied to claims 1-7, 9-11, 16 and 17 above, and further in view of Malvezzi et al. (Reproductive Biology and Endocrinology 2014, 12:121). The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. The teachings of Mallidis et al. and how they meet the limitations of claims 1-7, 9-11, 16 and 17 are outlined above in a preceding rejection and are hereby incorporated. The second factor to consider is to ascertain the differences between the prior art and the instant claims. Mallidis et al. do not teach the evaluation step includes further processing the sperm sample using density gradient centrifugation (DGC) or the sperm swim-up method, wherein these methods result in, for example, a 2-fold increase in progressively motile sperm.
Malvezzi et al. teach methods of processing sperm using three different DGC platforms to select “highly motile, morphologically normal spermatozoa with minimal DNA damage” (see p. 1, left column; p. 3, right column, 3rd paragraph). In addition, Malvezzi report that one of the DGC methods result in an approximately 1.5-fold increase in sperm motility (see p. 4, Table 1, SpermGrad-125 column). Incidentally, Malvezzi et al. report that both DGC and swim up results “in a superior population of highly motile and normal sperm” (see p. 5, right column, 3rd paragraph).
It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to modify the teachings of Mallidis et al. by further processing the sperm using DGC methods as taught in Malvezzi et al. because Malvezzi et al. teach DGC “improved %motility, TMS, %recovery and DNA damage, which supports previous evidence that density gradient can retrieve high quality motile sperm with little DNA damage”. Although the result reported in Malvezzi et al. is not quite a 2-fold increase, it still represents a significant increase in motile sperm. Further, the subjects in Malvezzi had normal sperm; the method could be expected to have more dramatic effects on sperm from infertile males. The person of ordinary skill in the art would have been motivated to use DGC because it is considered to be the “preferred technique for sperm processing for ART” (see abstract and p. 2, left column, 1st paragraph of Malvezzi and colleagues). Furthermore, the person of ordinary skill in the art could have reasonably expected success because of the improvement reported in the prior art with both sperm processing techniques, DGC and swim up.
Thus, the claims do not contribute anything non-obvious over the prior art.
Claims 19 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Mallidis et al. and Malvezzi et al. as applied to claims 1-7, 9-11 and 14-17 above, and further in view of Kaneko (US Patent 6,398,719). The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. The combined teachings of Mallidis et al. and Malvezzi et al. and how they meet the limitations of claims 1-7, 9-11 and 14-17 are outlined above in the preceding rejection and are hereby incorporated. The second factor to consider is to ascertain the differences between the prior art and the instant claims. The combined teachings of Mallidis et al. and Malvezzi et al. do not teach a method for carrying out an assisted reproductive technologies (ART) procedure using sperm that has been evaluated by the method of claim 15 with sperm processing (e.g., DGC), and further performing ART if the sperm is deemed useful in the ART procedure, namely, artificial insemination (AI), intra-uterine insemination (IUI) or in vitro fertilization embryo transfer (IVF-ET).
Kaneko teach a method of sperm washing and centrifugation used to process sperm prior to ART (see claims; column 1, lines 23-32). It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to modify the combined teachings of Mallidis et al. and Malvezzi et al. by performing ART following DGC because Malvezzi et al. suggested this at p. 2, left column, 1st paragraph: “[DGC] consistently produces samples of the highest quality required for intrauterine insemination and for in vitro fertilization (IVF)”. The person of ordinary skill in the art would have been motivated to use ART following sperm processing because Kaneko suggests that ART is the best option for male infertility and that the processing improves the insemination rate (see column 1, lines 23-32; column 6, lines 43-47). Furthermore, the person of ordinary skill in the art could have reasonably expected success because DGC and ART were well-established in the art as treatments for male infertility at the time of the filing of the invention.
Thus, the claims do not contribute anything non-obvious over the prior art.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Mallidis et al. as applied to claims 1-7, 9-11, 16 and 17 above, and further in view of Kaneko (US Patent 6,398,719). The first factor to consider when making a rejection under 35 U.S.C. 103(a) is to determine the scope and contents of the prior art. The teachings of Mallidis et al. and how they meet the limitations of claims 1-7, 9-11, 16 and 17 are outlined above in a preceding rejection and are hereby incorporated. The second factor to consider is to ascertain the differences between the prior art and the instant claims. Mallidis et al. do not explicitly teach treating the male subjects for infertility, although they did draw the controls from a population of males undergoing infertility investigations (see p. 2170 under “Subjects”).
Kaneko teach a method of sperm washing and centrifugation used to process sperm prior to assisted reproductive technologies (ART) (see claims; column 1, lines 23-32). It would have been obvious to the person of ordinary skill in the art at the time of the filing of the invention to modify the Mallidis et al. by performing ART because Mallidis et al. are studying a population of subfertile men. The person of ordinary skill in the art would have been motivated to use ART following sperm processing methods because Kaneko suggests that ART is the best option for male infertility and that the processing methods taught therein improve the insemination rate (see column 1, lines 23-32; column 6, lines 43-47). Furthermore, the person of ordinary skill in the art could have reasonably expected success because DGC and ART were well-established in the art as treatments for male infertility at the time of the filing of the invention.
Thus, the claims do not contribute anything non-obvious over the prior art.
Conclusion
No claim is allowed.
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/CHRISTINA M BORGEEST/Primary Examiner, Art Unit 1675