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 .
Priority
This application was filed Aug. 21, 2019, and is a 371 application of PCT/KR2018/002253 filed on Feb. 23, 2018, which claims benefit to the foreign application KR10-2017-0024657A, filed on Feb. 24, 2017. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. KR10-2017-0024657, filed on September 08, 2023.
Claim Status
In Applicant’s response, filed on Dec. 3, 2025, claim 1 is currently amended, claims 2, 4, and 7-8 are canceled, and claim 5 is withdrawn.
Applicant’s election without traverse of Group I (claims 1-4) in the reply filed on 04/01/2022 is acknowledged. Claim 5 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 04/01/2022.
Claims 1, 3, and 6 are currently under consideration.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 112
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, 3, and 6 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.
This rejection is a new rejection necessitated by amendments to the claims.
Regarding claim 1, the phrase "sufficient" renders the claim indefinite because it is unclear what amount or number of cells are part of the claimed invention. Claim 1 recites wherein “sub-culturing the primary cultured cells to obtain a sufficient number of cells for autologous or allogenic transplantation”. The term “sufficient” in claim 1 is a relative term, which renders the claim indefinite. The term “sufficient” 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 reasonable apprised of the scope of the invention. Thus, parameter of “sufficient” in the claim has been rendered indefinite and the dependent claims are also rejected because they depend on claim 1 and do not remedy the issue. See MPEP § 2173.05(b). Appropriate correction is required.
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, and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Nam et al, (U.S. Patent 8,815,581; App. No. 13/577,092; published 2014, previously presented) in view of Shimada, et al (Stroke 41.9: e552-e560, published 2010, previously presented), Keane et al., (US20170003303A1, published Jan. 2017), Pennartz, et al. (Journal of Visualized Experiments: JoVE 29: 1267, published 2009, previously presented), Watts et al. (MBio 6.5: e-11555-15, published 2015, previously presented), Gage et al (US 6,767,738, previously presented), Guo et al.( Nat Protoc., Nov;7(11):2005-12, published 2012, previously presented), as evidence by Kohnken, et al., (Comparative Medicine 66.2: 105-111, published 2016, previously presented), Sims, et al., (Nature protocols 3.7: 1228-1239, published 2008), and Florian, et al. (Stem Cell Migration: Methods and Protocols: 61-77, published 2011, previously presented).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on June 3, 2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
Regarding claim 1, Nam discloses a method for obtaining neural stem cells (see e.g. abstract, claims 1 and 3, fig. 1). Nam discloses neural stem cells are administered in a manner that permits them to graft or migrate to the intended tissue site and reconstitute or re-generate the functionally deficient area (i.e. transplantation)(see e.g. page 5, and col. 10). Further, Nam teaches that the cells can be transplanted directly into parenchymal or intrathecal sites of the central nervous system (see e.g. col. 10). Additionally, Nam teaches that the subculturing is performed three times to analyze early passage cells (see e.g. column 3 lines 9-15, Figure 3). Nam discloses a method comprising: collecting cells from brain tissue, treating the collected cells with collagenase and DNase I to isolate single cells, mixing the single cells with Percoll (i.e., a colloidal solution of silica coated with polyvinylpyrrolidone), and centrifuging the mixture to recover cells (see e.g. columns 11-12, Example 1), corresponding to the claim limitation of mixing the single cells in each tube with a medium for a density gradient centrifugation comprising a colloidal solution of silica coated with polyvinylpyrrolidone (i.e. Percoll). Nam discloses that the neural stem cells are used to treat CNS injuries such as stroke (see e.g. column 7 lines 40-56). Further, Nam teaches obtaining brain tissues by a surgical operation, and then mechanically cutting the tissue (see e.g. col. 11, Example 1).
Although Nam teaches the whole temporal lobe is collected, which includes the lateral ventricle (see e.g. col. 3-4, Example 1, fig. 1), Nam does not explicitly teach brain tissue in an outer ceiling area of a lateral ventricle from a stroke patient or describe the type of surgical operation.
However, the prior art of Shimada teaches collecting neural stem cells from the peri-infarct area, which includes tissues from the outer ceiling area of a lateral ventricle (see e.g. Abstract, fig. 4, p.e553 “Neural Stem/Progenitor Cell Isolation”). Claim Interpretation: The phrase “outer ceiling area” is not defined by Applicant’s specification and is being reasonable interpreted as cells lining and adjacent to the lateral ventricle.
Accordingly, it would have been obvious for one of ordinary skill in the art to combine the methods of isolating neural stem cells as taught by Nam et al. with the neural stem cells collected from the outer ceilings area of the lateral ventricles of a stroke patient as taught by Shimada because it was known in the prior art that the area around the lateral ventricles if a stroke patient would be enriched with neural stem cells. Further, Shimada teaches that the peri-infarct area is enriched with cells that have the ability to promote repair after central nervous system (CNS) injury (page e553, para. 1). Furthermore, a person of ordinary skill in the art would have a reasonable expectation of success because Nam and Shimada are both using known methods to obtain NSCs. Therefore, a person of ordinary skill in the art would have been able to combine similar neural stem cell methods with a reasonable expectation of success.
As stated supra, Nam teaches obtaining brain tissues by a surgical operation (see e.g. col. 3-4, Example 1, fig. 1). Further, Shimada discloses methods for dissection (see e.g. page e553). Both do not explicitly state that the surgical operation is being done for obtaining the tissue is a ventricular puncture.
Nevertheless, the prior art of Keane discloses that methods were known to a person of ordinary skill in the art for removing brain tissue (i.e. biological sample) from a person with traumatic brain injury (i.e. stroke) by ventriculostomy (i.e. ventricular puncture)(see e.g. para. 27, 54, and Example 3).
Accordingly, it would have been obvious for one of ordinary skill in the art to combine the methods as taught by Nam et al. with collecting brain tissue from a stroke patient by ventricular puncture taught by Keane because methods like ventriculostomy (i.e. ventricular punctures) were known in the prior art to be performed on a traumatic brain injury (i.e. stroke). Thus, a surgical operation like a ventricular puncture would have been obvious for a person of ordinary’s kill in the art to perform on a stroke patient with predictable results and a reasonable expectation of success.
Nam is silent with regard to collecting cells from about 1 gram of brain tissue.
However, the prior art of Pennartz discloses that it was known to obtain a single-cell suspension from neural tissues ranging from about .4 to about 1.6 grams (see e.g. page 1), corresponding to the claim limitation of collecting cells from about 1 g of brain tissue.
Further, the following is noted from the MPEP: MPEP 2144.05: “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).” MPEP 2144.05(I) teaches “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.” Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).” In regards to overlapping ranges, MPEP 2144.05(I) states, “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”, continuing in regards to ranges are close, “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)”.
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods of isolating neural stem cells as taught by Nam to incorporate the appropriate amount of brain tissue as taught by Pennartz because Pennartz teaches that about .4 grams of tissue may be isolated (see e.g. page 1), and that the method could be scaled up to accommodate the amount of brain tissue per tube (see e.g. page 1). Additionally, the prior art of Watts teaches that the maximal average tissue yield is obtained using 2 mice brains (i.e. about 1 gram) per Percoll gradient (see page 20). Moreover, Watts teaches that too much homogenized brain tissue per Percoll gradient overloads the gradient and result in a significant loss of yields (Supp. Material, page 2). Further, the prior art of Kohnken provides evidence that the average brain weight was 0.501 g for female mice and 0.492g for male mice (see fig. 1 legend), which reads on the claimed about 1 gram of brain tissue. Thus, a person of ordinary skill in the art would have only wanted to obtain the about 1 gram of tissue as taught by Pennartz and Watts as evidence by Kohnken and split the single cells into two or more tubes, which would have avoided the potential loss of neuronal cells and an overloaded Percoll gradient. Moreover, a person of ordinary skill in the art would have optimized the amount of brain tissue and single cells per tube based on the Percoll gradient, which would have led to predictable results with a reasonable expectation of success.
Nam does not explicitly state dividing the single cells into two or more tubes, mixing the single cells in each tube with Percoll at a v/v ratio of 2:1.
However, the prior art of Gage teaches a method of isolating stem cells derived from the central nervous system, specifically the step of mixing the single cells in a tube with Percoll at a v/v ratio of 2:1 (i.e., 65% NSC cells in media + 35% Percoll (column 14, Example 1, lines 43-58). Further, Gage subsequently teaches the step of dividing the single cells into two tubes and mixing the single cells in each tube with Percoll for density gradient centrifugation (col 15, lines 23-30).
Accordingly, it would have been obvious for one of ordinary skill in the art to modify the neural stem cell isolation methods as taught by Nam with the single cells in a tube with Percoll at a v/v ratio of 2:1 as taught by Gage because layering the cell suspensions in the Percoll gradient would ensure optimal separation of cells. A person of ordinary skill in the art would have combined the neural stem cell isolation methods of Nam with the mixing of the single cells with Percoll as taught by Gage because the 2:1 ratio allowed for layering of cell suspension with the Percoll gradient would ensure for optimal separation of cells based on the cell density. As stated supra, the prior art of Watts, teaches that too much homogenized brain tissue per Percoll gradient overloads the gradient and result in a significant loss of yields (Supp. Material, page 2). Furthermore, it has been held that discovering an optimum value of a result effective variable (i.e., ratio of Percoll) involves only routine skill in the art. In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980). In the instant case, dividing the brain tissue of Nam et al. into at least two tubes as taught by Gage would have avoided the potential loss of purified neuronal cells from an overloaded Percoll gradient. Therefore, a person of ordinary skill in the art would have optimized the ratio of cells mixed with Percoll in order to obtain an efficient density-based separation during centrifugation.
Regarding claim 1, Nam teaches that after Percoll based density centrifugation to remove red blood cells (i.e., red layer), the resulting cells were collected and resuspended (col 12, 1st para.).
Nam does not explicitly state that the cells are recovered from a white layer formed after the centrifugation.
However, the prior art of Gage teaches that after Percoll based density centrifugation, the upper and lower fractions adjacent to the red blood cells (i.e., red layer) were collected and resuspended (col 15, lines 42-46). Although Nam and Gage do not explicitly disclose the presence of a “white” layer, the fact that they collect all of the layers except the “red” RBC layer, reads on the claim limitation of collecting a white layer.
Accordingly, it would have been obvious for a person of ordinary skill in the art to have incorporated the step of collecting cells from a white layer formed after centrifugation as taught by Nam because Gage teaches collecting all of the layers except the RBC layers, as evidence by Sims which discloses that when isolating brain tissue using the Percoll density gradient that after centrifugation visible white brands appear (see e.g. fig. 2). Furthermore, an artisan of ordinary skill in the art of (i.e. isolating cells with Percoll) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007). In the instant case, incorporating the step of collecting the white layers as taught by Gage as evidence by Sims would have led to predictable results with a reasonable expectation of success because both teach methods of using Percoll with brain tissue.
Regarding claim 1, as stated supra, Nam discloses primary culturing and then sub-cultured (i.e. passaged)(see e.g. column 12, lines 3-14, lines 10-36, Figures 1A, Figures 2A, 2B, 3, Example 4,7). Further, Nam teaches subculturing is performed three times to analyze early passage cells (column 3 lines 9-15, Figure 3).
Nam is silent regarding sub-culturing is performed three times or less within two weeks to obtain a sufficient number of cells for autologous or allogenic transplantation.
However, the prior art of Guo discloses that neural stem cells (i.e. neurospheres) should form in about one week and teachings passaging every 2-3 days (see e.g. page 7; note: total of 13 days minimum). Further, Guo discloses culturing methods may be used for allogenic transplantation (see e.g. Example 6).
Further, the following is noted from the MPEP: MPEP 2144.05: “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).” MPEP 2144.05(I) teaches “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.” Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).” In regards to overlapping ranges, MPEP 2144.05(I) states, “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”, continuing in regards to ranges are close, “Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)”.
Accordingly, it would have been obvious for one of ordinary skill in the art to modify the neural stem cell methods as taught by Nam and incorporate the step of sub-culturing for three times within two week as taught Guo because early passaging of neural stem cells is important for maintaining viability. Further, Guo discloses that early passaging of neural stem cells avoids potential side effects that result from being in prolonged in vitro cultures (see e.g. page 7), as evidence by the prior art of Florian et al., which discloses that after 5-8 days in vitro neurospheres should appear, after 4-6 days in vitro neurospheres will have differentiated sufficiently, and that after approximately 10-14 days the NSC colonies will stop growing while others will expand (see e.g. page 68-72). Furthermore, Florian discloses that preparing a single cell solution from a neurospheres culture should preferably be of early passage primary cells, between 2 and 8 passages (see page 76). Therefore, a person of ordinary skill in the art would have a reasonable expectation of success combining the neural stem cell method (as taught by Nam) with the sub-culturing of three times within two weeks (as taught by Guo and Florian) because Nam, Guo, and Florian prefer all subculturing around three times to analyze early passaged cells (see e.g. Nam column 3 lines 9-15, Figure 3).
Regarding claim 3, Nam teaches wherein the primary culturing or the sub-culturing is
performed using an adherent culture method (column 12 Lines 10-36, Figures 1A, Figures 2A, 2B, 3).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant argues that in order to obtain human neural stem cells that can also be used for autologous transplantation, it is essential to collect the tissue from a region that has minimal impact on the patient (i.e. from an area where brain damage can be minimized), and that it is necessary to efficiently isolate neural stem cells from the acquired brain tissue and to expand them to a number sufficient for transplantation within a limited period of time (Remarks, page 7-8).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicants argument that in order to obtain human neural stem cells, there is not a claim limitation directed to “human” neural stem cells. Thus, Applicant arguments are not commensurate in scope with the claims. It is noted that Applicant assert that “expanding the cells to a number sufficient for transplantation within a limited period of time” is critical. However, the claim is directed to sub-culturing the primary cultured neural stem cells and the claim is not directed to expanding the cells in the claimed method. As discussed above in the 112 rejection the number of “sufficient” cells is relative and does not indicate the amount of cells needed for the autologous or allogenic transplantation. Furthermore, the claim is directed to the time period of sub-culturing and is not directed to the period of time for transplanting the neural stem cell in a subject (e.g. human or mammal). Thus, Applicant arguments are not commensurate in scope with the claims.
Applicant argues that the "outer ceiling area of the lateral ventricle" used in the present invention is an anatomical region that is bordered superiorly by the superior frontal white matter and laterally by the fronto-parietal cortex (Remarks, page 9). Further, Applicant argues that Shimada, provides no motivation to attempt to isolate neural stem cells from the "outer ceiling area of the lateral ventricle (Remarks, page 11).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
[AltContent: textbox ([img-media_image1.png]
Fig.4a of Shimada)][AltContent: textbox ([img-media_image2.png]
Applicants Image modified from Remarks, page 9)]In response to Applicants argument, it is noted that obtaining brain tissue from the specific region is important and presents a substantial risk to the patient. However, Applicant is not considering the breadth of the claimed “outer ceiling areas of the lateral ventricle.” As shown in the image from Applicants remarks (see above, and page 9), which has been modified to show the area of the lateral ventricles and the area that encompasses the outer ceiling. It is noted that the outer ceiling area of the lateral ventricle (highlight in yellow) includes the subventricular zone (SVZ)(see image above). It is noted that the claim does not recite a region that is between the “superior frontal white matter and laterally by the fronto-parietal cortex.” As discussed above, the prior art of Shimada teaches culturing cells from the peri-infarct area (see image below and fig. 4 of Shimada), which encompasses the outer ceiling area of the lateral ventricle, as discussed above. Therefore, it is unclear how Shimada provides no motivation to attempt to isolate neural stem cells from the outer ceiling area of the lateral ventricle because Shimada discloses that the “proximity of stroke injury to the lateral ventricle wall may determine whether there is a stem/progenitor cell response from the SVZ”, which suggests that a person of ordinary skill in the art would investigate isolating neural stem cells from a stroke patient that encompasses the outer ceiling area of the lateral ventricle.
Applicant asserts that “it is entirely unknown whether neural stem cells can be efficiently isolated from that region or that a person of ordinary skill in the art would not attempt to isolate neural stem cells using that region” (Remarks, page 9). Applicants argues that this region is approached through the course of ventriculostomy (Remarks, page 8-9).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicants argument that isolating stem cells from the outer ceiling area of the lateral ventricle is entirely unknown, Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references. In the instant case, Applicant has not provided prior art as evidence that isolating neural stem cells from the outer ceiling area of the lateral ventricle is entirely unknown. It is noted that the prior art of Azari (2010) teaches isolating neural stem cells from the periventricular region (outer ceiling area of the lateral ventricle)(see e.g. page 1-2) and cites the prior art of Morshead (1994) which discloses that the subependymal layer (i.e. outer ceiling area of the lateral ventricle) surrounds the lateral ventricle and encompasses neural stem cells (see e.g. pages 1071-1072, and fig. 1). Therefore, it is unclear how isolating stem cells from the outer ceiling area of the lateral ventricle is entirely unknown.
As discussed above, the prior art of Keane discloses that methods were known to a person of ordinary skill in the art for removing brain tissue (i.e. biological sample) from a person with traumatic brain injury (i.e. stroke) by ventriculostomy (i.e. ventricular puncture)(see e.g. para. 27, 54, and Example 3). Thus, a surgical operation like a ventricular puncture would have been obvious for a person of ordinary’s kill in the art to perform on a stroke patient with predictable results and a reasonable expectation of success.
Applicant argues that the prior art does not teach the number of cells obtainable after passaging within two weeks (i.e. the cells did not reach 108), which is the number required for transplantation (Remarks, page 10).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e. number of cells) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). As discussed above, there is not a claim limitation directed to the number of cells (i.e. the number of cells obtainable after passaging within two weeks reaching 108).
Applicant argues that Gage In fact, column 21 of Gage discloses with respect to three passages that, "By 4 weeks both cultures had been passaged 3 times." Accordingly, a skilled artisan could not predict from Gage a sufficient number of neural stem cells for transplantation can be obtained through passaging within two weeks.
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to the argument regarding Gage teaching three passages by 4 weeks, the prior art of Gage is note cited for teaching the number of passages or weeks. However, the prior art of Guo discloses that neurospheres (i.e. neural stem cells) should form in about one week and teachings passaging every 2-3 days (see e.g. page 7; note: total of 13 days minimum). Further, Guo discloses culturing methods that may be used for allogenic transplantation (see e.g. Example 6).
As discussed above, it would have been obvious for one of ordinary skill in the art to modify the neural stem cell methods of Nam and incorporate the sub-culturing of three time within two week as taught Guo because Guo discloses that early passage cell for neural stem cells avoid potential effects of the prolonged in vitro culture (see e.g. page 7). Furthermore, the prior art of Florian et al., discloses that after 5-8 days in vitro neurospheres should appear, after 4-6 days in vitro neurospheres will have differentiated sufficiently, and that after approximately 10-14 days the NSC colonies will stop growing while others will expand (see e.g. page 68-72). Thus, the prior art of Florian also discloses that preparing a single cell solution from a neurospheres culture should preferably be of early passage primary cells, between 2 and 8 passages (see page 76). Moreover, a person of ordinary skill in the art would have a reasonable expectation of success combining the neural stem cell method (as taught by Nam) with the sub-culturing of three times within two weeks (as taught by Guo and Florian) because Nam, Guo, and Florian prefer all subculturing around three times to analyze early passaged cells (see e.g. Nam column 3 lines 9-15, Figure 3). Therefore, a person of ordinary skill in the art would have combined similar methods for obtaining early passaging of NSC, which would have led to predictable results with a reasonable expectation of success. Furthermore, an artisan of ordinary skill in the art of (i.e. culturing of neural stem cells) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Applicant argues that Watts does not disclose brain tissue of the outer ceiling area of the lateral ventricle (Remarks page 12). Applicant argues that Kohnken merely discloses that the weight of a single mouse brain is approximately 0.5 g but contains no disclosure whatsoever regarding brain tissue of the outer ceiling area of the lateral ventricle, nor of isolating neural stem cells from such tissue (Remarks, page 12). Applicant argues that Fischer is a paper concerning a method for isolating adult neural stem cells for research purposes and relates only to isolating neural stem cells from the SEZ region, and does not teach neural stem cells usable for transplantation from brain tissue obtained from a patient (Remarks, page 12-13). Applicant asserts that Pennartz is only a paper relating to a method for isolating single cells from mouse brain tissue and discloses the use of 400 g of brain tissue, and the use of the gentle MACS program in order to isolate single cells with minimal damage (Remarks page 12).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to Applicant arguments regarding the prior art references (i.e. Shimada, Watts, Kohnken, Fischer, Pennartz) and their deficiencies, it is noted that the test for obviousness is not whether the features of a secondary reference maybe bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413,208 USPQ 871 (CCPA 1981). In the instant case, as stated supra, the prior art of Nam discloses a method for obtaining neural stem cells (see e.g. abstract, claims 1 and 3, fig. 1) that are administered in a manner that permits them to graft or migrate to the intended tissue site and reconstitute or re-generate the functionally deficient area (i.e. transplantation)(see e.g. page 5, and col. 10), and teaches that the subculturing is performed three times to analyze early passage cells (see e.g. column 3 lines 9-15, Figure 3).
Applicant argues that Guo is a paper relating to a method for isolating adult neural stem cells and discloses Guo also discloses that cells are passaged every 2-3 days and that early cells (<p10) are used for differentiation experiments. However, Guo contains no disclosure whatsoever that a sufficient number of neural stem cells can be obtained for transplantation within two weeks (Remarks, page 13).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
Applicants are reminded that the test for obviousness is not whether the features of a secondary reference maybe bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413,208 USPQ 871 (CCPA 1981). In the instant case, Guo discloses that cells are passaged every 2-3 days and that early cells (<p10) are used for differentiation experiments. As discussed above, the claim limitation of “sufficient” is a relative term and does not indicate an amount that is needed for autologous or allogenic transplantation. Further, it is noted that the cell just needs to be obtained for autologous or allogenic transplantation and the transplantation does not have to be performed within two weeks.
Applicant argue that Florian is a paper relating to a method for isolating adult neural stem cells and discloses a method of isolating neural stem cells from the SVZ region and the DG region of the hippocampus, both of which are known as sites of active neurogenesis (Remarks, page 13). Applicant argues that none of the cited references disclose, nor do they provide any motivation of, isolating neural stem cells from the "outer ceiling area of the lateral ventricle" that can be obtained during surgery in stroke patients because unlike the SVZ, SEZ, hippocampus, or DG, the outer ceiling area of the lateral ventricle is not known as a major neurogenic niche in the adult brain but rather corresponds to a safe margin from which tissue can be obtained without impairing functionally important regions. (Remarks, page 13).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
Applicants are reminded that the test for obviousness is not whether the features of a secondary reference maybe bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413,208 USPQ 871 (CCPA 1981). In the instant case, Florian discloses that preparing a single cell solution from a neurospheres culture should preferably be of early passage primary cells, between 2 and 8 passages (see page 76). As discussed above, a person of ordinary skill in the art would have a reasonable expectation of success combining the neural stem cell method (as taught by Nam) with the sub-culturing of three times within two weeks (as taught by Guo and Florian) because Nam, Guo, and Florian prefer all subculturing around three times to analyze early passaged cells (see e.g. Nam column 3 lines 9-15, Figure 3). Furthermore, the claims read on “comprising” which does not exclude other embodiments (i.e. other cells from other regions that connect to the outer ceiling area of the lateral ventricle), such as the addition of isolating adult neural stem cells for transplantation as claimed (see MPEP 2111.03).
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Nam et al, (U.S. Patent 8,815,581; published 2014, previously presented) in view of Shimada, et al (Stroke 41.9: e552-e560, published 2010, previously presented), Keane et al., (US20170003303A1, published Jan. 2017), Pennartz, et al. (Journal of Visualized Experiments: JoVE 29: 1267, published 2009, previously presented), Watts et al. (MBio 6.5: e-11555-15, published 2015, previously presented), Gage et al (US 6,767,738, previously presented), Guo et al.( Nat Protoc., Nov;7(11):2005-12, published 2012, previously presented), as evidence by Kohnken, et al., (Comparative Medicine 66.2: 105-111, published 2016, previously presented), Sims, et al., (Nature protocols 3.7: 1228-1239, published 2008), and Florian, et al. (Stem Cell Migration: Methods and Protocols: 61-77, published 2011, previously presented), as applied to claims 1 and 3 above, and further in view of Walker et al (Journal of Visualized Experiments, 84: e51225; published 2014, previously presented).
This rejection is a new rejection necessitated by amendments to the claims. However, since it is substantially similar to a rejection set forth in the non-final Official action mailed on June 3, 2025, therefore any aspect of applicant's response considered relevant to the rejection as newly set forth is responded to following the statement of rejection.
The teachings of Nam et al. apply here as indicated above.
Regarding claim 6, although Nam teaches the accumulated number of stem cells significantly increases as the number of passages increases (col 7, line 25, col 10, line 8).
In regard to claim 6, Nam et al., does not explicitly teach that the number of cells increases by 10-fold after each round of sub-culturing.
However, Walker demonstrates that proliferation and/or differentiation of neural stem cells (NSC) from the brain naturally divide about 10-fold per passage (Figure 3; page 8, see “Representative Results”, page 9, para. 2).
Accordingly, it would have been obvious for one of ordinary skill in the at the time of the invention to obtain NSCs from the lateral ventricle of a subject and increase the number of cells significantly between each passage as suggested by Nam et al. and observe a 10-fold increase in said cells as disclosed by Walker with a reasonable expectation of success. One of ordinary skill in the art would have done so in order to ensure that a sufficient amount of cells was able to be obtained for transplantation (column 10 lines 48-60). Thus, is would have been a natural feature of these cells to divide 10-fold as disclosed by Walker and it would have been an obvious feature to desire in the taught cells as disclosed by Nam.
Furthermore, in regard to claim 6 , it is noted that the "wherein the number of cells increases by 10-fold after each round of sub-culturing" clause does not recite any additional active method steps, but simply states a characterization or conclusion of the results of process step positively recited (e.g. subculture of NSC isolated from the lateral ventricles). Therefore, the "wherein" clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.").
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant argues that “as mentioned previously, Nam, Shimada, Fischer, Pennartz, Watts, Kohnken, Gage, Guo, and Florian do not teach or suggest each and every element of the instant claims, and Walker does not cure this deficiency. Specifically, Nam, Shimada, Fischer, Pennartz, Watts, Kohnken, Gage, Guo, Florian, and Walker do not disclose, nor do they provide any motivation of, isolating neural stem cells from the "outer ceiling area of the lateral ventricle" that can be obtained during surgery in stroke patients. The present invention provides for the first time a clinically feasible method that enables the safe acquisition of brain tissue during surgery in stroke patients and the rapid and sufficient expansion of neural stem cells for transplantation within two weeks. This outcome is not only unexpected but also highly significant for clinical application and is thus inventive” (Remarks, page 14).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In submitting evidence asserted to establish unobvious results, there is a burden on an applicant to indicate how the examples asserted to represent the claimed invention are considered to relate to the examples intended to represent the prior art and, particularly, to indicate how those latter examples do represent the closest prior art. See In re Borkowski, 595 F.2d 713, 184 USPQ 29 (CCPA 1974); In re Goodman, 339 F.2d 228, 144 USPQ 30 (CCPA 1964). It should also be established that the differences in the results are in fact unexpected and unobvious and of both statistical and practical significance. In re Merck, 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986); In re Longi, 759 F. 2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Klosak, 455 F2d 1077, 173 UAPQ 14 (CCPA 1972); In re D’Ancicco, 429 F.2d 1244, 169 USPQ 303 (CCPA 1971 ). Ex parte Gelles, 22 USPQ2d 1318 (BPAI 1992).
The arguments addressing the references individually is addressed above. In the instant case, the Applicant is reminded that the breadth of the recitation of the "outer ceiling area of the lateral ventricle." As discussed above, the prior art of Shimada teaches collecting neural stem cells from the brain tissue of a stroke patient (see e.g. Abstract, p.e553 “Neural Stem/Progenitor Cell Isolation”). It is noted that the claim is not limited to a specific subject (i.e. human or animal). As discussed above, Shimada collects tissues from the peri-infarct area which includes tissue from the “outer ceiling area” of a lateral ventricle. Note that the phrase “outer ceiling area” is not defined by Applicant’s specification and is being reasonable interpreted as cells lining and adjacent area of the lateral ventricle.
It is noted that the invention is clinically feasible, and the outcome of the method is not only unexpected but also highly significant for clinical application and is thus inventive. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Therefore, it is not clear that Applicant’s asserted unexpected results are unexpected in view of the prior art. As discussed above the amount of “sufficient” and does not relate to a specific number of cells and has been held to be indefinite when the claim fails to state the function which is to be achieved, and more than one effect can be implied from the specification or the relevant art. In re Fredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). In instant case, the claim does recite a sufficient number of cells nor does the specification indicate a sufficient number of cells for autologous or allogenic transplantation.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
No claim is 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.
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JOSEPHINE GONZALES
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/ Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631
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