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 .
Response to Arguments
The Applicant has provided a response to the Non-Final Office Action, dated 11/19/2025. In the response the Applicant has provided amendments to the claims and arguments drawn to the objections and rejections. Based upon the claim amendments, all of the claim objections are withdrawn. Similarly, the claim amendments have provided for a withdrawal of the 35 USC 112(b) rejection.
On page 7 of the Applicant’s Arguments, the Applicant asks for the Examiner to point out where in the specification there are active hyperlinks. In the instantly filed specification, there are 2 hyperlinks associated with the bibliography at the end of document. Specifically, reference number 9, on page 52, line 27; reference number 18, page 53, line 11 (these are provided in paragraph [0238] of the PGPub).
On pages 8 and 9 of the Applicant’s Arguments, the Applicant points to the references used in the 35 USC 101 rejection and state that they do not embed the claimed neurosphere and do not teach glioblastoma cells. With respect to the former, although it was not discussed in the 35 USC 101 rejection, it was discussed in the 35 USC 103 rejection that Herrera-Perez teaches embedding the cells in a matrix that is consistent with that claimed. See page 2574, “Cell culture in 3D matrices” section. However, based upon IDS references, and other prior art references, it appears as though performing invasion assays on embedded cancer cells continues to be known in the art. See Tamaki, et al (Journal of Neurosurgery, 87, 602-609, 1997 [IDS Reference]), page 602 and 603, “Materials and Methods” section. With respect to the latter, as discussed in the rejection, the prior art does not need to explicitly teach glioblastoma, because it would be clear and obvious to the ordinary artisan that a brain cancer invasion assay can support any brain cancer; the Applicant does not provide a reasonable argument as to why this is an inappropriate assumption.
On page 10 of the Applicant’s Arguments, the Applicant states that the combination of Brooks with Herrera-Perez would render Brooks inoperative. First, there is nothing in the prior art, or the rejection that requires that the filter be removed, and as such, this is not a reasonable argument as to why Brooks would be inoperative. Second, the rejection is not based on what Brooks explicitly tells the ordinary artisan, but what Brooks teaches the ordinary artisan about measuring tumor invasiveness. The ordinary artisan possesses ample knowledge and applied skill in the instant field of endeavor and the rejection must consider what the ordinary artisan would be expected to know. See MPEP 2141.03.
On page 11 of the Applicant’s Arguments, the Applicant asserts that the prior art does not “measure the area” of the neurospheres. When considering how to interpret this limitation, since there is no reference to how the measurement must be performed, there is absolutely nothing prohibiting the ordinary artisan from providing an image of the neurosphere, which would inherently include its area, and comparing this image to another neurosphere, thereby measuring and comparing the two areas; even if the comparison is purely subjective, this difference would inform the ordinary artisan as to how invasive the cells are. This determination is entirely consistent with the broadest reasonable interpretation of claimed steps c), e), and f). Herrera-Perez provides an image of the embedded neurospheres at different time-points, wherein scale bars are included. Between the series of images, and the fact that scale bars can be used to provide an objective measure of area, it appears as though the reference teaches the claimed limitation. As discussed above, one must understand that the ordinary artisan is not strictly limited to the words printed on the prior art reference, as the Examiner must consider the level of skill that the ordinary artisan would be expected to have. This “level of skill” would include all of the education and applied skills that the ordinary artisan has used and learned.
The Applicant has provided amendments to the claims that have allowed for the 35 USC 112(b) rejection and the objections to the claims to be withdrawn. The objection to the specification has been maintained, and the location of the hyperlinks has been described. The 35 USC 101 rejection is maintained, although it will be modified to include other references that further describe the claimed embedded limitation. The 35 USC 103 rejections are maintained for all of the previously described reasons. Although the 35 USC 101 rejection will be modified, this action will be final, because the rationale of the rejection has not changed; the provided references continue to establish that the claimed method should be considered routine, conventional, and well-understood.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
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 17-35 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claim(s) recite(s) an in vitro method of diagnosing, and determining invasiveness of glioma. This judicial exception is not integrated into a practical application because the claims are drawn to a well-understood, routine, and conventional diagnostic method, without providing any instructions for a particular treatment. See MPEP 2106.04(d)(2).
Independent claims 17 and 28 both appear to be drawn to a conventionally used, but slightly modified, assay referred to as the “Matrigel invasion assay.” See Brooks, et al (Methods in Molecular Medicine: Metastasis Research Protocols, Volume 2; Humana Press, New Jersey, 2001), Chapter 7, pages 61-70. In fact, these invasion assays are commercially manufactured by companies like Becton Dickinson, and have been specifically used with glioblastoma-based neurospheres. See Valster, et al (Methods, 37, 208-215, 2005), page 212, “Transwell invasion assay” section. Similarly, these types of invasion assays can include embedded cells. See Herrera-Perez, et al (Tissue Engineering: Part A, 21, 2572-2582, 2015), page 2574, “Cell culture in 3D matrices” section; Tamaki, et al (Journal of Neurosurgery, 87, 602-609, 1997 [IDS Reference]), page 602 and 603, “Materials and Methods” section; Vinci, et al (Journal of Visualized Experiments, 99, e52686, 2015), page 2, “3D Tumor Spheroid Invasion Assay” section; Hellwig, et al (Toxicology in Vitro, 52, 106-115, 2018), page 108, sections 2.2 and 2.3. Since there are no claimed steps beyond the conventionally used Matrigel invasion assay, and all of the non-assay steps are considered mental steps, the claim as a whole does not integrate a practical application, and as such the claims do not appear to be eligible under 35 USC 101.
For the full analysis of the claims under 35 USC 101, the Applicant is directed to MPEP 2106, and particularly the flow chart in 2106(III). With respect to the flow chart, the claims are drawn to a method, and as such, are included in one of the statutory categories (step 1). The claims provide for a method of diagnosing a disease, wherein the claimed method appears to be the same as the well-known Matrigel invasion assay, wherein the claimed cells have been used in this method. As such, this method must be considered well-understood, routine, and conventional (step 2A of the flow chart). See MPEP 2106.05(d). Since the active steps are considered routine, the additional steps must be considered to determine if the claims provide for a step that integrates the conventional method into a practical application (step 2B of the flow chart). Beyond the steps drawn to the invasion assay, steps c), e), and f) are drawn to “measuring,” and “determining.” But these limitations must be considered “mental processes,” and as such, do not provide for a practical application. See MPEP 2106.04(a). When considering Vanda Pharm. Inc. v. West-Ward Pharm. Int’l Ltd., 887 F.3d 1117, 126 USPQ2d 1266, for example, it is noted that the claims provide for a method of determining a patient’s risk for a particular drug, by determining the level of a drug metabolite/biomarker in the subject, following administration of the drug; Vanda would have been ineligible, but for the fact that the claim also provides for a practical application of the acquired data, wherein the artisan can determine safe amounts of said drug.
Although claim 32 does describe therapies, this claim does not provide for a practical application, since the claim provides for a broad limitation that does not inform the artisan of any specific modifications to treatments or treatment regimens based upon the acquired “invasion score.”
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.
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 17-35 are rejected under 35 U.S.C. 103 as being unpatentable over Brooks, et al (Methods in Molecular Medicine: Metastasis Research Protocols, Volume 2; Humana Press, New Jersey, 2001) and Herrera-Perez, et al (Tissue Engineering: Part A, 21, 2572-2582, 2015). As discussed above, Brooks provides for a protocol for a Matrigel invasion assay. Brooks generally describes the steps for the assay, but does not teach or suggest using glioblastoma cells in the neurosphere. However, Brooks is clear that the method is for investigating tumor invasion, and as such, any invasive tumor would be obvious to use. See page 61, 2nd and 3rd paragraph.
Herrera-Perez specifically uses the Brooks protocol with glioblastoma stem cells. See page 2572, “Abstract” section. This supports the assertion that the ordinary artisan would find any invasive tumor to be an obvious choice, including the cells claimed in the instant method.
With respect to claims 17 and 28, Brooks generally teaches the claimed protocol. See page 67 and 68. However, the ordinary artisan is aware the general protocols can be reasonably and predictably modified, in order to support certain cell-types or investigations. For example, Herrera-Perez provides for a similar, but somewhat modified version of Brooks’ protocol, wherein Herrera-Perez polymerizes Matrigel around the glioblastoma neurospheres. See page 2574, “Cell culture in 3D matrices” section. Herrera-Perez’s neurospheres appear to be consistent with the claimed neurospheres. See page 2573, “Cell liquid culture” section. Both Brooks and Herrera-Perez teach some form of embedding. Brooks suggests any number of hours, from 12 or more. See page 67, “The Matrigel Invasion Assay,” step 3. Herrera-Perez teaches the claimed temperature. See page 2574, “Cell culture in 3D matrices” section. Both references explicitly describe observing the level of invasion, and making calculations with respect to these observations.
With respect to claims 18, 21 and 33-35, the prior art teaches Matrigel. This material fulfils all of the claim limitations.
With respect to claim 19, Brooks rehydrates Matrigel, and Herrera-Perez does not state the amount of protein in the Matrigel solution. However, between the fact that Matrigel is a routinely used cell substrate, and the Matrigel invasion assay is a routine assay, would suggest that the claimed amount of protein would either be obvious to the ordinary artisan, or an optimizable parameter.
With respect to claim 20, Herrera-Perez teaches the polymerization of a Matrigel solution around the neurosphere. See page 2574, “Cell culture in 3D matrices” section.
With respect to claims 22 and 23, Herrera-Perez states that the cells are acquired from a surgically excised tumor. See page 2573, “Cell liquid culture” section. This section appears to fulfill the claimed method steps.
With respect to claim 24, although it is unclear if the glioblastoma cells are diffuse midline glioma stem cells, neither Brooks nor Herrera-Perez put any limitation on the tumor cell-type that could be used in the invasion assay. Since Herrera-Perez generally describes glioblastoma stem cells, there is reasonable expectation that subtypes of these cells would also work.
With respect to claims 25-27, 29 and 30, Herrera-Perez appears to provide data that would be consistent with the claimed data. The calculation of invasiveness would be obvious to the ordinary artisan.
With respect to claim 31, although it is unclear if the glioblastoma cells are diffuse midline glioma stem cells, neither Brooks nor Herrera-Perez put any limitation on the tumor-type that can be diagnosed. Since any invasive tumor would be obvious, and it is clear that glioblastoma stem cells are compatible with the assay, the claimed cancer would be obvious.
With respect to claim 32, the ordinary artisan in this situation would be an oncologist. It would be obvious to create or modify a treatment regimen, based upon new data regarding a tumor’s invasiveness.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID W BERKE-SCHLESSEL whose telephone number is (571)270-3643. The examiner can normally be reached M-F 8AM-5:30PM.
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, Melenie Gordon can be reached at 571-272-8037. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID W BERKE-SCHLESSEL/Primary Examiner, Art Unit 1651