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 1, 2, 6-8, and 12-14 are currently pending.
Claims 1, 2, 6, and 7 are amended.
Claims 12-14 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claims 3-5 and 9-11 remain cancelled.
Claims 1-2 and 6-8 have been considered on the merits.
New and Maintained Rejections Necessitated by Amendment
Claim Objections
Claims 1 and 7 are objected to because of the following informalities: The claims are missing a period at the end. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-2 and 6-8 are newly rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 1 recites a new limitation of “wherein the at least one stable cell line of at least one valve interstitial cell comprises at least one male-derived stable cell line and at least one female-derived stable cell line, each capable of independently recapitulating sex-specific osteogenic differentiation and calcification responses, including differential responses to sex hormones, in the cell culture-based valve calcification assay”. There does not appear to be any support for this limitation in the specification. The specification does not contain the term “male”, “sex”, or any term which connects the claimed cell lines with a sex classification. The specification contains the term “female” a single time at [0030] which defines a biological sample and states “as used herein, a “biological sample” may contain…female ejaculate…”, which is related in no way to the claimed material. Further, the specification is wholly silent to “recapitulating sex-specific” responses. The specification does not contain the term “hormone” at any point. Therefore, there does not appear to be any support for this limitation within the disclosure. This is a new matter rejection.
Claim 2 recites the new limitation of “wherein the at least two valve interstitial cells comprise at least one male-derived valve interstitial cell and at least one female-derived valve interstitial cell such that direct comparison of sex-specific calcification responses is enabled within the same assay”. The specification does not contain the term “male”, “sex”, or any term which connects the claimed cell lines with a sex classification. The specification contains the term “female” a single time at [0030] which defines a biological sample and states “as used herein, a “biological sample” may contain…female ejaculate…”, which is related in no way to the claimed material. Therefore, there does not appear to be any support for this limitation within the disclosure. This is a new matter rejection.
Claim 6 recites the new limitation of “wherein said pathological process further recapitulates sex-specific differences in valve calcification observed clinically in human patients with calcific aortic valve disease, including greater calcification in male-derived valve interstitial cells relative to female-derived valve interstitial cells under equivalent osteogenic conditions, and differential calcification responses to sex hormones including estrogen and dihydrotestosterone”. The specification does not contain the term “male”, “sex”, “estrogen”, “dihydrotestosterone”, or any term which connects the claimed cell lines with a sex classification. The specification contains the term “female” a single time at [0030] which defines a biological sample and states “as used herein, a “biological sample” may contain…female ejaculate…”, which is related in no way to the claimed material. The specification does not at any point describe independently assessing the assay based on sex, nor testing or evaluating equivalent osteogenic conditions between female and male cell lines. Therefore, there does not appear to be any support for this limitation within the disclosure. This is a new matter rejection.
Claim 7 recites the new limitation of “wherein the at least one stable cell line of at least one valve interstitial cell comprises at least one male-derived stable cell line and at least one female-derived stable cell line, and wherein the at least one potential treatment compound is independently assessed for its effect on calcification in the male-derived stable cell line and the female-derived stable cell line to identify sex-specific inhibitory or promotional effects on valve calcification, including differential dose- dependent responses to the at least one potential treatment compound in male-derived and female-derived valve interstitial cells”. The specification does not contain the term “male”, “sex”, or any term which connects the claimed cell lines with a sex classification. The specification contains the term “female” a single time at [0030] which defines a biological sample and states “as used herein, a “biological sample” may contain…female ejaculate…”, which is related in no way to the claimed material. The specification does not at any point describe independently assessing the assay based on sex, nor testing or evaluating differential dose-dependent responses between female and male cell lines. Therefore, there does not appear to be any support for this limitation within the disclosure. This is a new matter rejection.
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.
Claim(s) 1, 2, and 6-8 remain rejected under 35 U.S.C. 103 as being unpatentable over Zabirnyk et al (Vascular Pharmacology 122–123 (2019) 106583) (reference of record), Bowler et al (Am J Physiol Heart Circ Physiol 315: H1614–H1626, 2018)(reference of record).
Regarding claim 1, Zabirnyk teaches cell culture-based valve calcification assay by employing valve interstitial cells (VIC), isolated from patients with and without signs of valve calcification, to a novel calcification treatment compound, SNF472, and evaluating its inhibition of calcification as required by claims 1, 7 and 8 (Abstract, lines 1-4). The assay is completed by separating VICs into osteogenic media, basic growth media, and variable treatment concentration groups with SNF472 as required by claim 2 (pg. 2, column 2, lines 20-24). Zabirnyk teaches that at least one media is a standard growth media serving as a control, thereby enabling direct comparison of calcification between the osteogenic and control conditions within the same assay as required by the newly amended limitations of claim 2 (pg. 2, col. 2, para 3). Calcification is seen in the osteogenic media group due to “applying osteogenic media to the at least one valve interstitial cell to promote differentiation and calcification… for a period of at least seven days” as required by claims 1, 6 and 7 (Fig. 4A; demonstrates 1, 2, 3 week application of osteogenic media). This addresses the limitation of exhibiting at least one pathological process causing aortic and mitral valve calcification as required by claims 6 and 7 because the instant claim 7 teaches that this process is induced in the same manner as the art (i.e. inducing through osteogenic media application), therefore the art teaches the at least one pathological process causing valve calcification induced by the application of osteogenic media to the at least one stable cell line of at least one valve interstitial cell in the cell culture, wherein said pathological process recapitulates in vivo aortic valve and mitral valve calcification mechanisms. Zabirnyk teaches staining using Alizarin Red to assess the calcification as required by claim 1 and 7 (pg. 2, column 2, para 4). Further, Zabirnyk teaches the quantification, which meets the limitation of detecting a presence or absence of at least one calcific cellular nodule, of the stain spectrophotometrically, which meets the limitation of being performed by computer-assisted morphometric analysis software of a digital image as required by claims 1 and 7 (pg. 2, column 2, para 4). Zabirnyk also teaches that the stained cells are photographed in a photomicrograph as required by clam 1 (Fig. 1). Zabirnyk teaches that a “SNF472 blocked calcification even when calcification was ongoing. However, the present study showed that the effect was more pronounced the earlier the agent was given, suggesting it is important to initiate treatment with SNF472 as early as possible in order to inhibit or limit the calcification process (pg. 4, column 1, lines 21-22). Zabirnyk teaches that the tested compound was identified as inhibiting calcification in the at least one stable cell line of at least one valve interstitial cell are candidates for further testing in models of valve disease as required by the newly amended claim 7 (pg. 4).
Zabirnyk does not explicitly teach that the quantification of the photomicrograph is expressed as an area of the stain binding divided by a total area shown by the photomicrograph as required by claim 1. However, Zabirnyk presents Fig. 2A which plots the relative calcification as a percent, and states “Calcification was measured by Alizarin red staining and quantified spectrophotometrically. (A) Relative calcification, values are dot plots + mean.” (Fig. 2). This data demonstrates expressing the area of the stain binding divided by a total area shown in the photomicrograph and subsequently represented as a percent calcification as required by claim 1.
Zabirnyk does not teach that the cells used are a stable cell line obtained from an adult Ts(H2-K1-tsA58) mouse of at least two months of age, also known as the Immortomouse as defined by the specification, as required by claim 1 and 7. Zabirnyk does not teach the newly added limitation of claim 1 and claim 7 requiring “wherein the at least one stable cell line of at least one valve interstitial cell is a conditionally immortalized cell line capable of extended in vitro propagation at a permissive temperature of approximately 33 degrees Celsius in the presence of interferon-gamma while retaining capacity to undergo valve interstitial cell differentiation in vitro”. Zabirnyk does not teach the newly added limitation of claim 1 requiring “wherein the at least one stable cell line of at least one valve interstitial cell is distinct from primary human valve interstitial cells and from primary non-immortalized murine valve interstitial cells”. Zabirnyk does not teach the newly added limitation of claim 1 requiring “wherein the at least one stable cell line of at least one valve interstitial cell comprises at least one male-derived stable cell line and at least one female-derived stable cell line, each capable of independently recapitulating sex-specific osteogenic differentiation and calcification responses, including differential responses to sex hormones, in the cell culture-based valve calcification assay”. Zabirnyk does not teach the newly added limitation of claim 2 and 7 requiring “wherein the at least two valve interstitial cells comprise at least one male-derived valve interstitial cell and at least one female-derived valve interstitial cell such that direct comparison of sex-specific calcification responses is enabled within the same assay”. Zabirnyk does not specifically describe the sex of the cells employed as stated therefore Zabirnyk does not explicitly teach “wherein said pathological process further recapitulates sex-specific differences in valve calcification observed clinically in human patients with calcific aortic valve disease, including greater calcification in male-derived valve interstitial cells relative to female-derived valve interstitial cells under equivalent osteogenic conditions, and differential calcification responses to sex hormones including estrogen and dihydrotestosterone” as required by newly amended claim 6 and 7.
However, Bowler teaches a similar embodiment to that of Zabirnyk where calcification of VICs is evaluated from Immortomice. Bowler teaches that VICs are isolated from 8 week old adult Immortomice as required by claim 1 and claim 7 (pg. 2, col. 2, para 1-2). Bowler also teaches that the immortalized cell line can theoretically be expanded indefinitely however they chose to limit passage number to 30 which meets the limitation of a “stable cell line” as required by claim 1 and 7 (pg. 2, Col. 2, para 1-2). The limitation of a “stable cell line” is further met by Fig. 1B which demonstrates three separate adult Immortomouse-derived VIC cell lines which each stably express one of the following genotypes: WT CDH11, a heterozygous knockout of CDH11, and a homozygous knockout of CDH11as required by claim 1 (Fig. 1B). Additionally, Bowler teaches the use of Alizarin red stained slides in which the calcification fractions were calculated as the ratio of positive calcification pixel to the total number of valve leaflet pixels, which meets the limitations of claim 1 because the pixels of Bowler are a measurement of area of the photomicrograph.
Regarding the newly added limitation of claim 1 and claim 7 requiring “wherein the at least one stable cell line of at least one valve interstitial cell is a conditionally immortalized cell line capable of extended in vitro propagation at a permissive temperature of approximately 33 degrees Celsius in the presence of interferon-gamma while retaining capacity to undergo valve interstitial cell differentiation in vitro”. This limitation is an inherent capability of the cells taught by Bowler and does not require this limitation be taught because a step of culturing the cells with interferon-gamma at 33 degrees Celsius is merely claimed as a “capability” and not an active step. Regardless, Bowler teaches “to allow for sustained immortal growth” the cells are cultured in “immortomedia” which expressly contains interferon-gamma and the culture is completed at 33 degrees Celsius (pg. 2, col. 2, para 2).
Regarding the newly added limitation of claim 1 requiring “wherein the at least one stable cell line of at least one valve interstitial cell is distinct from primary human valve interstitial cells and from primary non-immortalized murine valve interstitial cells”. Bowler teaches that the at least one stable cell line of at least one valve interstitial cell an immortalized valve interstitial cell which is a distinct cell type from a primary human valve interstitial cell and from a non-immortalized murine valve interstitial cell (pg. 2, col. 1, last para spanning para 2 of col. 2).
Regarding the newly added limitation of claim 1 requiring “wherein the at least one stable cell line of at least one valve interstitial cell comprises at least one male-derived stable cell line and at least one female-derived stable cell line, each capable of independently recapitulating sex-specific osteogenic differentiation and calcification responses, including differential responses to sex hormones, in the cell culture-based valve calcification assay”. Bowler teaches multiple mice from which VICs are obtained including both female and male cells (Table 1/Table 2). The phrase “each capable of independently recapitulating sex-specific osteogenic differentiation and calcification responses, including differential responses to sex hormones, in the cell culture-based valve calcification assay” is a recitation of an inherent capability of the claimed cell lines, therefore, the male/female cell lines of Bowler would be inherently capable of recapitulating sex-specific responses due to the fact that they are genetically male or female.
Regarding the newly added limitation of claim 2 and 7 requiring “wherein the at least two valve interstitial cells comprise at least one male-derived valve interstitial cell and at least one female-derived valve interstitial cell such that direct comparison of sex-specific calcification responses is enabled within the same assay”. Bowler teaches multiple mice from which VICs are obtained including both female and male cells (Table 1/Table 2). The phrase “each capable of independently recapitulating sex-specific osteogenic differentiation and calcification responses, including differential responses to sex hormones, in the cell culture-based valve calcification assay” is a recitation of an inherent capability of the claimed cell lines, therefore, the male/female cell lines of Bowler would be inherently capable of recapitulating sex-specific responses due to the fact that they are genetically male or female.
Regarding the newly added limitation of claim 6 and 7 requiring “wherein said pathological process further recapitulates sex-specific differences in valve calcification observed clinically in human patients with calcific aortic valve disease, including greater calcification in male-derived valve interstitial cells relative to female-derived valve interstitial cells under equivalent osteogenic conditions, and differential calcification responses to sex hormones including estrogen and dihydrotestosterone”. Bowler teaches multiple mice from which VICs are obtained including both female and male cells (Table 1/Table 2). The phrase “each capable of independently recapitulating sex-specific osteogenic differentiation and calcification responses, including differential responses to sex hormones, in the cell culture-based valve calcification assay” is a recitation of an inherent capability of the claimed cell lines, therefore, the male/female cell lines of Bowler would be inherently capable of recapitulating sex-specific responses due to the fact that they are genetically male or female.
One of ordinary skill in the art would find it obvious to combine the cell-culture based calcification assay taught by Zabirnyk with the VICs isolated from Immortomice taught by Bowler. The motivation to combine would be that Bowler teaches “[w]ith the number of calcific aortic stenosis patients expected to double by 2050, and possibly triple by 2060 (12, 40), there is a need for a better understanding of the biological mechanisms driving CAVD to develop well-tolerated, noninvasive pharmacological therapies for valvular calcification” (pg. 1, column 2, lines 10-15). One of ordinary skill in the art would have a reasonable expectation of success because Bowler teaches the comprehensive method of isolating the VICs from the Immortomice for use in calcification assays.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 02/23/2026 have been fully considered but they are not persuasive.
Applicant argues (Remarks, pg. 8, para 1) that the newly amended limitation of claim 1 requiring that the cells are derived from “2-month-old adult” mice “directly distinguishes the claimed cell line from the Bowler reference, in which VICs were isolated from 8-week-old immortomice”.
In response, this argument is not found persuasive. 8 weeks is 2 months. Applicant states in their arguments that “while 8 weeks approximates 2 months, the specification at paragraph [0079] specifically identifies the 2-month-old adult source”. This is not found persuasive since any ordinary artisan, or even layperson, would understand that 8 weeks is 2 months. Additionally, Bowler teaches specifically that the mice that are used to derive the valve interstitial cell lines are derived from 8-week-old mice (pg. 2, col. 2, para 2). Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 8, para 2 and pg. 10, last para spanning pg. 11) that Zabirnyk does not teach the VICs derived from the Immortomouse and specifically grown in the presence of interferon-gamma at 33 degrees Celsius.
In response, this argument is not found persuasive, Zabirnyk is not replied upon to teach the limitation of the VICs derived from the Immortomouse, rather Bowler is.
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).
Additionally, Bowler teaches regarding the newly added limitation of claim 1 and claim 7 requiring “wherein the at least one stable cell line of at least one valve interstitial cell is a conditionally immortalized cell line capable of extended in vitro propagation at a permissive temperature of approximately 33 degrees Celsius in the presence of interferon-gamma while retaining capacity to undergo valve interstitial cell differentiation in vitro”. This limitation is an inherent capability of the cells taught by Bowler and does not require this limitation be taught because a step of culturing the cells with interferon-gamma at 33 degrees Celsius is merely claimed as a “capability” and not an active step. Regardless, Bowler teaches “to allow for sustained immortal growth” the cells are cultured in “immortomedia” which expressly contains interferon-gamma and the culture is completed at 33 degrees Celsius (pg. 2, col. 2, para 2).
Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 13-14) that Bowler does not employ the VICs isolated from the Immortomouse in a cell culture based valve calcification assay. Further that Bowler employs the alizarin red staining on 12 month old cells isolated from non-immortomice.
In response, the argument is not found persuasive. Bowler is not relied upon to teach either of these limitations, Zabirnyk is.
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).
Zabirnyk teaches cell culture-based valve calcification assay by employing valve interstitial cells (VIC), isolated from patients with and without signs of valve calcification, to a novel calcification treatment compound, SNF472, and evaluating its inhibition of calcification as required by claims 1, 7 and 8 (Abstract, lines 1-4). Zabirnyk teaches staining using Alizarin Red to assess the calcification as required by claim 1 and 7 (pg. 2, column 2, para 4). Further, Zabirnyk teaches the quantification, which meets the limitation of detecting a presence or absence of at least one calcific cellular nodule, of the stain spectrophotometrically, which meets the limitation of being performed by computer-assisted morphometric analysis software of a digital image as required by claims 1 and 7 (pg. 2, column 2, para 4). Zabirnyk also teaches that the stained cells are photographed in a photomicrograph as required by clam 1 (Fig. 1). Therefore, the arguments are not found persuasive.
Applicant argues (Remarks, pg. 14-15) that the cited references do not individually constitute an anticipatory reference. Applicant states that Zabirnyk demonstrates the assay method with primary cells and not with a cell line and that Bowler demonstrates Immortomouse-derived VICs but does not demonstrate their use in the instantly claimed model.
In response, this argument is not found persuasive. 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). Zabirnyk teaches cell culture-based valve calcification assay by employing valve interstitial cells (VIC), isolated from patients with and without signs of valve calcification, to a novel calcification treatment compound, SNF472, and evaluating its inhibition of calcification as required by claims 1, 7 and 8 (Abstract, lines 1-4). Bowler teaches a similar embodiment to that of Zabirnyk where calcification of VICs is evaluated from Immortomice. Bowler teaches that VICs are isolated from 8 week old adult Immortomice as required by claim 1 and claim 7 (pg. 2, col. 2, para 1-2). Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 15-16) that the motivation to combine Zabirnyk with Bowler is insufficient.
In response, this argument is not found persuasive. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, The motivation to combine would be that Bowler teaches “[w]ith the number of calcific aortic stenosis patients expected to double by 2050, and possibly triple by 2060 (12, 40), there is a need for a better understanding of the biological mechanisms driving CAVD to develop well-tolerated, noninvasive pharmacological therapies for valvular calcification” (pg. 1, column 2, lines 10-15). This motivation is sufficient because Zabirnyk demonstrates a valve calcification assay which required obtaining the valves from human hearts, “Healthy valves were collected from explanted hearts of heart transplant recipients without a history of heart valve disease and with macroscopically normal valves” (Zabirnyk, pg. 2, col. 1, para 6). Therefore, the assay of Zabirnyk does not use readily available VICs since they are required to be taken from a very specific subset of humans undergoing heart transplant but that still contain healthy valves and this is completed in an invasive manner. The Immortomouse derived VICs have the benefit of being more readily available which is taught by Bowler in the cited motivation of “[w]ith the number of calcific aortic stenosis patients expected to double by 2050, and possibly triple by 2060 (12, 40), there is a need for a better understanding of the biological mechanisms driving CAVD to develop well-tolerated, noninvasive pharmacological therapies for valvular calcification” (pg. 1, column 2, lines 10-15). Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 16, para 2) that the invention is novel and non-obvious because “the significance of this discovery lies in providing a mouse VIC calcification assay that enables candidate drugs identified in vitro to be subsequently tested in genetic and experimental in vivo mouse models of valve disease”.
In response to applicant's argument that the invention is novel and non-obvious because the results of the assay could provide motivation for further research in an in vivo assay, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 16, last para) that the reliance on Bowler to demonstrate calculation of calcification fractions as the ratio of positive calcification pixels to total valve leaflet pixels is not correct because Bowler was imaging cells excised from murine aortic valves and not specifically the results of this assay.
In response, this argument is not found persuasive. As a first response, the concept of calculating the total stained area relative to total area in general is an extraordinarily basic mathematical concept employed in nearly all and any areas of scientific research.
As a second response to applicant’s argument, Zabirnyk does not explicitly teach that the quantification of the photomicrograph is expressed as an area of the stain binding divided by a total area shown by the photomicrograph as required by claim 1. However, Zabirnyk presents Fig. 2A which plots the relative calcification as a percent, and states “Calcification was measured by Alizarin red staining and quantified spectrophotometrically. (A) Relative calcification, values are dot plots + mean.” (Fig. 2). This data demonstrates expressing the area of the stain binding divided by a total area shown in the photomicrograph and subsequently represented as a percent calcification as required by claim 1.
Further, the fact that Zabirnyk performs the basic area calculation without explicitly describing the steps of calculating a basic area calculation cannot be the basis of novelty of the claimed invention.
Further yet, Bowler demonstrates the use of Alizarin red stained slides in which the calcification fractions were calculated as the ratio of positive calcification pixel to the total number of valve leaflet pixels, which meets the limitations of claim 1 because the pixels of Bowler are a measurement of area of the photomicrograph. Although this calculation may have been completed on murine aortic valves, it does not render the basic area calculation wholistically inapplicable due to “materially different contexts” as asserted by Applicant.
Thus, both Zabirnyk and Bowler employ the basic mathematical concept of calculating area stained respective to total area.
Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 118) that the instant claims are novel over Zabirnyk, novel over Bowler, and novel over the combination of Zabirnyk and Bowler.
In response, the arguments are not found persuasive because Applicant’s arguments are drawn to the alleged deficiencies of each references specifically and not the combination of the references. 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 (Remarks, pg. 18-21) that the instant invention provides unexpected results because of the clinically significant capabilities of observing sex-specific differences in the cell lines claimed.
In response, this argument is not found persuasive. As a first point the new limitations of the claims related to male/female/sex differences are not supported in any way by the instant disclosure. The specification, drawings, and originally filled claim set do not at any point describe sex differences. Please see the new matter rejections presented above for a more detailed explanation of how the disclosure does not disclose these limitations.
Further, all of these limitations are provided as wherein clauses which describe the capabilities of the cells of the Immortomouse, meaning they are inherent to the Immortomouse. Each limitation is addressed within the maintained 35 U.S.C. 103 rejection above. Further, Bowler teaches both male and female VIC cell lines derived from the Immortomouse (Tables 1 and 2). Thus, the cells of Bowler would inherently have the capabilities claimed.
Therefore, the argument is not found persuasive.
Applicant argues (Remarks, pg. 22-23) that each reference does not individually teach all the claimed limitations of the claims.
In response, the arguments are not found persuasive because Applicant’s arguments are drawn to the alleged deficiencies of each references specifically and not the combination of the references. 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.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached on 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632
Prosecution Insights