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 .
DETAILED ACTION
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 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.
Response to Amendments
Applicant’s amendments, corrected drawings, Declaration submitted under 37 C.F.R. §1.132 by Nelson Alexander, Ph.D. filed on Jan. 13, 2026, IDSs submitted on Jan. 5, 2026, Mar. 17, 2026 and Apr. 7, 2026, and response filed Jan. 8, 2026 have been received and entered into the case.
Status of the Claims
Claims 1-4, 6-20, 22 and 23 are currently pending.
Claims 1, 3, 7, 11, 13 and 17 are amended.
Claims 13-20 and 22 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.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 5 and 21 are cancelled.
Claim 23 is new.
Claims 1-4, 6-12 and 23 have been considered on the merits.
Drawing Objections
The drawing objections are withdrawn due to amendment.
Claim Rejections - 35 USC § 112(a)
The claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ), are withdrawn due to amendment.
Claim Rejections - 35 USC § 112(b)
The claim rejections under 35 USC § 112, (b) or second paragraph (pre-AIA ), are withdrawn due to amendment. New claim rejections under 35 USC § 112, (b) or second paragraph (pre-AIA ) have been added to address the claim amendments.
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.
Claim 6 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 6 is rendered indefinite since claim 1, from which claim 6 depends from limits the obtained surgical resection tissue sample to one that is not derived from a formalin-fixed paraffin-embedded sample, whereas claim 6 requires the obtained surgical resection tissue sample to be derived from a formalin-fixed paraffin-embedded sample. Therefore, the metes and bounds of claims are rendered vague and indefinite. For the purposes of compact prosecution, claim 1 will be interpreted to include both types of surgical resection tissue samples, either derived formalin-fixed paraffin-embedded or not.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
New claim rejections under 35 USC § 112, (d) or fourth paragraph (pre-AIA ) have been added to address the claim amendments.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 1 limits the obtained resection tissue sample to one that is not derived from a formalin-fixed paraffin-embedded sample whereas claim 6 requires the obtained resection tissue sample to be derived from a formalin-fixed paraffin-embedded sample. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The claim rejections under 35 USC § 102 are revised due to amendment.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 6-12 and 21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jordanova et al. (American Journal of Clinical Pathology, 2003) (ref. of record).
With respect to claim 1, Jordanova teaches preparing a diffuse B-cell lymphoma samples (representative samples) for analysis (abstract). With respect to step a of claim 1, Jordanova teaches obtaining tissue samples from tumors of human subjects (surgical resection tissue samples or biopsy samples) which were formalin-fixed (pg. 328 Col. 1 para. 2). Joranova teaches the samples are lymphomas which contain tumor and normal tissue (would be understood to include solid tumor masses and lymph nodes) (pg. 332 para. 2). Please note that claim 1 is being interpreted to include both types of surgical resection tissue samples, either derived formalin-fixed paraffin-embedded or not derived formalin-fixed paraffin-embedded as explained in the rejection under 35 U.S.C. §112(b). With respect to step b of claim 1, Jordanova teaches digesting the samples, then mechanical treating the samples by mincing with pipette tip, filtering the samples, then resuspending the cells in a buffer to form a single-cell suspension (mechanically blending the obtained surgical resection tissue sample to provide a representative sample, where any heterogeneity of cells within the obtained surgical resection tissue sample is substantially homogeneously distributed within the representative sample) (pg. 328 Col. 1 para. 3-4). Jordanova teaches generating a single-cell suspension, therefore, any heterogeneity of the separated cells should be uniformly distributed within the homogenized sample.
With respect to claims 2 and 9, Jordanova teaches the method further comprising analyzing the cells by flow cytometric analysis and loss of heterozygosity (LOH) analysis by PCR of extracted DNA from sorted cells (analyzing and/or measuring one or more biomolecules of the cells with at least a first aliquot of the representative sample) (pg. 328 Col. 1 para. 3 to pg. 329 Col. 1 para. 3).
With respect to claim 3, Jordanova teaches analyzing and/or measuring one or more biomolecules of the cells involves performing cytometric analysis, sequence analysis, and fluorescent in situ hybridization (FISH) analysis (immunoenzymatic analysis) (pg. 328 Col. 1 para. 3 to pg. 329 Col. 2 para. 1).
With respect to claim 6, Jordanova teaches cutting two sections from the formalin-fixed paraffin-embedded tissue samples to be processed and homogenized (pg. 328 Col. 1 para. 2 to Col. 2 para. ).
With respect to claims 7 and 8, Jordanova teaches generating a solution containing dissociated cells using filtering and then sorting and purifying the cells using flow cytometry (pg. 328 Col. 1 para. 3).
With respect to claims 10-12, Jordanova teaches sorting the cells by flow cytometry based on the expression of CD79a (a cell surface marker) by first adding an anti-CD79a antibody to the cell suspension, then a fluorescent secondary antibody, and subjecting the cell suspension to flow cytometry and sorting (pg. 328 Col. 1 para. 3 to Col. 2 para. 3).
Although, Jordanova does not explicitly teaches that any aliquot removed from the representative sample comprises one or more populations of subclones at a proportion at which they existed within the obtained surgical resection tissue sample as recited in claim 21, Jordanova teaches the claimed method of homogenizing tumor surgical resected tissue sample and generating a single-cell suspension, therefore, any appropriate sized aliquot should contain one or more populations of subclones at a proportion at which they existed within the obtained surgical resection tissue sample.
Therefore, the reference anticipates the claimed subject matter.
Claim Rejections - 35 USC § 103
The claim rejections under 35 USC § 103 are withdrawn due to amendment. New claim rejections under 35 USC § 103 have been added to address the claim amendments.
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 1-3, 7-12 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Garaud et al. (Journal of Visualized Experiments, 2014) (ref. of record) as evidenced by Khattar (“Dissociate Tissues for Cell Recovery”, May 13, 2015) (ref. of record) in view of Mørkve et al. (Cytometry: The Journal of the International Society for Analytical Cytology, 1991) (ref. of record).
With respect to claim 1, Garaud teaches a method of preparing a tissue homogenate to be analyzed or a representative sample for analysis (abstract). With respect to step a) of claim 1 and claims 23, Garaud teaches obtaining dissect resected tissue from a subject including tumor tissue where the sample size is 100 to 10,000 mm3 (1-10 cm3) (pg. 2 steps 1 and 2). With respect to step a) of claim 1, Garaud teaches the tissue sample is fresh and, therefore, it is not derived from a formalin-fixed paraffin-embedded sample or embedded in paraffin (pg. 2 Section 1 step 1). With respect to step b) of claim 1, Garaud teaches mechanically dissociating the surgical resection tissue sample using a mechanical dissociator which is essentially a blender as evidenced by Khattar (pg. 2 Section 1 steps 4-7). Khattar reports that the gentleMACS Dissociator pictured in Garaud is a blender (pg. 1). Although, Garaud does not explicitly teaches that the heterogeneity of the cells within the obtained homogenate from the tissue sample is homogenously distributed within the representative sample and that any aliquot removed from the representative sample comprises one or more populations of subclones at a proportion at which they existed within the obtained surgical resection tissue sample as recited in step b) of claim 1, Garaud teaches the claimed method of homogenizing a tumor surgical resected tissue sample. Furthermore, Garaud teaches generating a single-cell suspension, therefore, any heterogeneity of the separated cells should be uniformly distributed within the homogenized sample.
Garaud does not teach the method where the surgical resection tissue is fixed as recited in step a) of claim 1. However, Mørkve teaches a similar method of preparing a representative sample for analysis including flow analysis where the sample is fresh or fixed (abstract). Mørkve teaches a method of preparing a representative sample for analysis including flow analysis where the sample is fresh or fixed (abstract). Mørkve teaches mechanical blending the tumor tissue with surgical blades to generate a suspension (pg. 623 Col. 1 para. 4-5). Additionally, Mørkve teaches that tissue fixed in paraformaldehyde showed no difference from fresh tissue (abstract). Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method of Garaud to include fixed surgical resection tissue samples for the benefit of being able to analyze additional tissue samples. It would have been obvious to one of ordinary skill in the art to make such a modification, since fixing tumor tissue samples and analyzing such samples was known in the art as taught by Mørkve. Additionally, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of Garaud to include fixed surgical resection tissue samples and the step of fixing the obtained surgical resection tissue samples, since similar methods of analyzing surgical resection tissue were known to use fixed tissue as taught by Mørkve.
With respect to claims 2, 10 and 11, Garaud teaches staining a portion of the homogenate or representative sample for the presence CD45+ or EpCAM+ (one or more biomarkers that are cell surface markers ) and quantifying a number of EpCAM+ (tumor cells) and a number of leukocytes (immune cells) within the at least the portion of the homogenate (representative sample) (pg. 3 para. 2 and Fig. 3). With respect to claim 3, Garaud teaches analyzing and measuring of the stained cells by flow cytometric analysis (pg. 3 para. 2 and Fig. 1).
With respect to claims 7 and 8, Garaud teaches processing the representative sample or homogenate to generate a single cell solution for flow cytometric analysis (pg. 1 last para., pg. 2 Section 2 steps 1-5, pg. 3 para. 2, and Fig. 1). With respect to claim 9, Garaud teaches the method where the dissociated cells and biomolecules derived from the dissociated cells are analyzed by qRT-PCR (polymerase chain reaction) (pg. 3 last para.)
Further with respect to claims 10-12, Garaud teaches (i) isolating intact cells from at least a portion of the representative sample; (ii) staining at least a portion of the isolated intact cells; and (iii) sorting the stained isolated intact cells into two or more populations of stained isolated intact cells (pg. 3 para. 2 and Fig. 3).
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.
Claim 4 is rejected under 35 U.S.C. 103(a) as being unpatentable over Garaud as evidenced by Khattar in view of Mørkve (as applied to claims 1-3, 7-12 and 23 above), and further in view of Russnes et al. (Journal of Clinical Investigation, 2011) (ref. of record).
The teachings of Garaud and Mørkve can be found in the previous rejection above.
Garaud does not teach the method where at least one clinical decision is determined based on the analyzing and/or measuring the one or more biomolecules of the cells and where the decision is determining disease prognosis, predicting recurrence of disease, identifying subjects for inclusion within clinical trials or determining a therapeutic treatment strategy as recited in claim 4.
However, Russnes teaches making a clinical decision based on the genetic analysis of tumors (the analysis and/or measuring of one or more biomolecules of tumor cells) including disease prognosis, predicting recurrence of disease and determining a therapeutic treatment strategy (abstract, Fig. 4 and pg. 3816 Col. 1 last para. to Col. 2 last para.).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method of Garaud to include a step of making a one of the clinical decisions listed in claim 4, for the benefit of using the data generated from the representative sample as taught by Russnes. It would have been obvious to one of ordinary skill in the art to include the determining of at least one clinical decision based on the analyzing and/or measuring the one or more biomolecules of the cells and where the decision is determining disease prognosis, predicting recurrence of disease, identifying subjects for inclusion within clinical trials or determining a therapeutic treatment strategy, since similar methods analyzing tumor samples were known to make such decisions as taught by Russnes. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification to the method of Garaud, since clinical decisions based on tumor samples that have been analyzed or have had a biomolecule measured were known at the time of filing as taught by Russnes.
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.
Double Patenting
The nonstatutory double patenting rejections are withdrawn due the filing of a terminal disclaimer to U.S. Patent No. 11,959,838.
Response to Arguments
Applicant's arguments filed Jan. 8, 2026 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. § 103, Applicant argues that Jordanova and/or Chu do not teach a method where the tissue samples are fixed and not paraffin embedded (Remarks pg. 8 para. 1). Applicant argues that Jordanova teaches formalin-fixed paraffin embedded (FFPE) tissue blocks and Chu is directed to an instrument to extract biological molecules from tissue samples without damaging them where the tissue samples are frozen or FFPE (Remarks pg. 8 para. 2-3). Applicant argues that Fig. 11 of Chu demonstrates that the tissues samples are either frozen or FFPE tissue samples and all of the working examples disclosed in Chu use FFPE samples (Remarks pg. 8 last para. to pg. 9 para. 2). Applicant argues that as explained in the declaration submitted by Dr. Alexander, the microtome device used in Chu requires that the tissue specimen be fixed so that thin sections can be made and there is no disclosure in Chu to use samples other than those that have been frozen or fixed and embedded (Remarks pg. 9-10 bridging para.). Applicant argues that Dr. Alexander explains there are no examples or protocols in Chu for using fixed, non-embedded surgical resection samples as claimed (Remarks pg. 10 para. 2). Applicant argues that Dr. Alexander explains the skilled artisan would understand based on the materials and methods section of Chu that the samples that are fixed would be paraffin embedded (Remarks pg. 10 para. 3). Applicant argues that the Chu’s reference to tissue section implies that the samples were fixed and paraffin embedded, since the slice are thin and made using a microtome and Example 2 is describing a thin section of fixed and paraffin embedded tissue that was placed on a glass slide following the use of a microtome (Remarks pg. 11 para. 2). Applicant argues there is no motivation to combining Jordanova’s paraffin-based homogenization with Chu’s general mention of other fixatives to arrive at the claimed metho, since Chu does not providing a teaching on a maintain cellular morphology or achieve a substantially homogenous distribution of cells from a fixed resection tissue sample that has not been embedded (Remarks pg. 11 para. 3).
The majority of Applicant’s arguments are directed to Chu not teaching surgical resection tissue sample that is not derived from a formal-fixed paraffin-embedded sample. Applicant’s arguments with respect to Chu have been considered but are moot because the arguments do not apply to any of the references being used in the current rejections. The amendments to the claims required a new grounds of rejection and different art to address the newly added claim 23. Additionally, the Applicant’s amendments limiting claim 1 so that the surgical resection tissue sample is not derived from a formal-fixed paraffin-embedded sample necessitated new grounds of rejections. Applicant’s arguments are drawn to Jordanova and Chu failing to teach this new limitation. However, this new limitation is addressed in the new rejections.
Response to Evidentiary Declaration under 37 CFR §1.132
The declaration of Nelson Alexander, Ph.D filed on Jan. 13, 2026 under 37 CFR §1.132 has been considered but is ineffective to overcome the rejections of claims.
Dr. Alexander explains that the claimed invention solves the problem of preparing a representative sample from a heterogenous tissue sample with a homogenate that includes a substantially homogeneously distributed cellular structure (Declaration para. 3). However, it is maintained that this feature is taught in the prior art by Jordanova and Garaud.
Dr. Alexander explains that Chu does not teach samples which are fixed and not paraffin embedded and the fixed tissue samples taught by Chu are embedded (Declaration para. 5 and 12). Dr. Alexander explains that Chu is directed to an non-destructive macromolecule extraction device used to extract biological molecules from tissue sections without damaging them and that the device can be used for FFPE samples (Declaration para. 6-7). Dr. Alexander further explains that the skilled artisan would understand that the ethanol-fixed and formalin fixed tissues used in 0030 and 0120 and Fig. 7 would be paraffin-embedded as well, since the “Materials and Methods” section of Example 2 describes embedding the fixed tissue and Fig. 11 only includes either frozen or FFPE tissue samples (Declaration para. 8-10). Dr. Alexander states that 0030 of Chu has been incorrectly interpreted in the office action as disclosing fixed tissue which has not been embedded, but the fixed tissue in 0030 has been paraffin embedded so that it can be sectioned into thin slices using a microtome and this would not be possible without being embedded in paraffin (Declaration para. 11).
The majority of Dr. Alexander’s remarks are directed to Chu not teaching surgical resection tissue sample that is not derived from a formal-fixed paraffin-embedded sample. Dr. Alexander’s remarks with respect to Chu have been considered but are moot because the arguments do not apply to any of the references being used in the current rejections. The amendments to the claims required a new grounds of rejection and different art to address the newly added claim 23.
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 EMILY ANN CORDAS whose telephone number is (571)272-2905. The examiner can normally be reached on M-F 9:00-5:30 EST.
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/EMILY A CORDAS/Primary Examiner, Art Unit 1632
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