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 .
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.
Claim(s) 36-44 and 46-50 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stone et al (2016) (citation 23 on the IDS of 07/17/2026) in view of Van Raemdonck et al (2014) (citation 23 on the IDS of 07/17/2026), Snyder et al (2011) (citation 21 on the IDS of 07/17/2026), Goncalves-Primo et al (2014) (citation 5 on the IDS of 07/17/2026) and Norton et al (2013) (citation 14 on the IDS of 07/17/2026).
Relevant to the limitations of claim 36, Stone et al teaches a method of preparing amplified DNA released from a potential graft including: extracting cell-free, graft derived DNA from a sample of perfusate that was in contact with the potential graft ex-vivo (e.g.: p.231 – Perfusion; p.232 – Sample Collection During EVNP; DNA extraction); preparing amplified DNA from the extracted cf-DNA (e.g.: p.232 - Quantitative Polymerase Chain Reaction); and assessing the amplified DNA as a measure of quantity of total cf-DNA (e.g.: Figure 4). Relevant to claim 36 as it requires determining suitability of the graft for transplantation, Stone et al teaches that increasing concentrations in cell-free DNA were observed suggesting cell death, and that all kidneys functioned within normal parameters and met the criteria for transplantation at the end of perfusion (e.g.: p.230 – Results). Relevant to the limitations of claim 36 as it requires removing contaminating cells from the sample prior to extracting cf-DNA, Stone et al teaches that DNA was extracted from plasma samples of the perfusate, where plasma is a liquid component of blood that is free of blood cells, and the reference specifically teaches that perfusate samples were centrifuged at 2000g for 5 minutes, which is a step sufficient to remove cells (e.g.: p.232 - Sample Collection During EVNP).
Relevant to claim 37, Stone et al teaches obtaining the potential graft (e.g.: p.231 – Procurement of donor organs).
Relevant to claims 38-40, Stone et al teaches measuring the amount of total cf-DNA in perfusate from multiple time points, and provides a graph which is a visual comparison of the amounts at different time points (e.g.: p.232- Perfusate; Figure 4).
Relevant to claim 41, Stone et al teaches measuring cf-DNA amounts using quantitative polymerase chain reactions performed using a QuantStudio 12K Flex system with Power SYBR green PCR master mix, which is a real-time PCR system.
Relevant to claims 46 and 47 Stone et al teaches graft organs from pigs.
Stone et al exemplifies a method in which genomic DNA is quantified in a sample as a measure of total DNA associated with initiation and maintenance of proinflammatory response and immune activation. Stone et al does not specifically teach an analysis that provides a measure particularly directed to the detection of graft-specific cf-DNA, or the analysis of a graft organ that is a lung, or a prefusion solution that is a buffered extracellular solution comprising dextran 40 and human albumin (relevant to claim 36). However, the successful use of such perfusate solutions, and solution with additional red blood cells, in for the ex vivo perfusion of lungs was known in the art and is taught by Van Raemdonck et al.
Van Raemdonck et al teaches a variety of conditions that are used for the technique of ex vivo organ perfusion in transplantation. Relevant to the requirements of the instantly rejected claims, Van Raemdonck et al teaches methods that include the use of Steen Solution, which is a buffered, extracellular solution with the addition of human albumin to maintain optimal colloid pressure and dextran 40 to protect the endothelium from complement- and cell-mediated injury and to inhibit coagulation and platelet aggregation (e.g.: p.644, right col; p.648, left col). Van Raemdonck et al teaches that Steen solution may be supplemented with red blood cells (p.644 - EVLP technique and protocols; Table 1).
Relevant to the limitations of the claims as they require quantifying amounts of graft-specific cf-DNA, Snyder et al teaches the use of next generation sequencing (relevant to claim 42) to detect and quantify donor-specific cell free DNA in a sample of blood from a transplant recipient (e.g.: Figure 1). Relevant to the limitations of the claims as they require assessing graft-specific cf-DNA, Snyder teaches that and donor-specific DNA (analogous to the graft-specific DNA recited in the claims) is measured using donor-specific bases (e.g.: p.6231 – right col; Table 1).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date the instantly rejected claims to have performed the analysis of cell-free DNA in an ex-vivo perfusate sample as taught by Stone et al, on perfusate samples from lung graft organs that are perfused with a buffered, extracellular solution with human albumin, dextran 40 and additional red blood cells, as taught Van Raemdonck et al. The skilled artisan would have been motivated to use the perfusate and organs exemplified by Van Raemdonck et al based on the expressed teachings of Van Raemdonck et al that such reagents allow for the preservation, assessment and reconditioning of ideal, questionable, and unacceptable donor lungs prior to transplantation, and may increase the number of suitable grafts, reduce the incidence of primary and late graft dysfunction, and improve outcome after organ transplantation.
Where Van Raemdonck et al renders obvious a perfusate with additional red blood cells, and Stone et al teaches that genomic DNA in perfusate is associated with initiation and maintenance of proinflammatory response and immune activation, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date the instantly rejected claims to have performed the graft-specific cell-free DNA detection of Snyder et al on the perfusate sample rendered obvious by Stone et al in view of Van Raemdonck et al to assess a quantity of graft-specific (i.e.: donor derived) cell-free DNA in the sample in addition to the methods of total DNA measurement of Stone et al. The skilled artisan would be motivated to use the next generation sequencing of Snyder et al based on the expressed teachings of Snyder et al that the method can accurately and efficiently detect donor derived DNA in a mixture of both donor and non-donor DNA fragments (akin to the perfusion fluid comprising additional red blood cells taught by Van Raemdonck et al), as well as measure total DNA in the sample (as taught by Stone et al), and the teaching of Stone et al that DNA released from the donor organ is suggestive of cell death in the donor organ. Where Stone et al teaches that the release of endogenous DNA, and the detection of increased amounts of extracellular DNA, is associated with initiation and maintenance of proinflammatory response and immune activation related to graft damage, it would be obvious for the skilled artisan to construe increasing amounts of cell-free DNA in the perfusate as an indication that the graft is becoming decreasingly suitable (claim 43), and decreasing amounts of cell-free DNA in the perfusate as an indication that the graft is becoming increasingly suitable (claim 44).
Stone et al in view of Van Raemdonck et al and Snyder et al, as detailed above, does not specifically provide for the quantification of short (75-170 base pairs) fragments indicative of apoptosis and long (500-15,000 base pairs) fragments indicative of cell lysis (claim 36), or the quantifying of cell lysis (claimd 48 and 50), comparing the amount of lysis at different times (claim 49). However, Stone et al teaches that cell-free DNA suggests cell death, and the detection of pre-transplantation graft apoptosis as a marker of post-transplant graft functionality, as well as the distribution of nucleic acid fragment sizes that result from apoptosis versus cell lysis, were known in the art at the time the invention was made.
Relevant to the instantly rejected claims, Goncalves-Primo et al teaches the detection of biomarkers of apoptosis (e.g.: BAX/BCL2 ratio) in preimplantation biopsies from graft organs, and the association of an increased BAX/BCL2 ratio (indicative of increased apoptosis) with a higher risk of delayed graft function (e.g.: Figure 3).
Additionally, while Stone et al teaches that cell-free DNA in perfusate-derived samples suggests cell death in the potential graft tissue, Norton et al teaches that cell-free DNA in a blood sample may be the result of cellular apoptosis, or may be the result of genomic DNA released from nucleated cells as the result of cell damage. Additionally, Norton et al teaches that apoptosis-derived fragments are typically <200 bp in length, whereas the DNA that results from cellular damage is >300 bp in length (e.g.: p.1562; p.1564). Relevant to the limitations of claims 48 and 49, Norton teaches the analysis of gDNA derived from cell damage at different time points (e.g.: Fig 1) similar to the time point analysis of cfDNA in perfusate taught by Stone et al. Relevant to claim 50, Norton et al teaches quantification of apoptosis- (i.e.: pDNA) and cell damage- (i.e.: gDNA) derived nucleic acids using ddPCR.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date the instantly rejected claims to included a determination of an amount of cell lysis using an analysis of the nucleic acid fragments, as taught by Norton et al, in the perfusate sample analysis rendered obvious by Stone et al in view of Van Raemdonck et al and Snyder et al. The skilled artisan would be motivated to analyze the nucleic acid fragments of Stone et al because while Stone et al teaches that nucleic acid in perfusate is a marker of cell death in a graft, Norton et al teaches that cell-free DNA in a sample can be the result of either apoptosis (i.e.: cell death) or the release of genomic DNA from cell damage (i.e.: lysis). The skilled artisan would furthermore be interested in establishing that any cell-free DNA in a perfusate sample is the result of apoptosis based on the expressed teachings of Goncalves-Primo et al that apoptosis in a potential graft can indicate an increased risk for delayed graft function. Where Norton et al teaches that apoptosis-derived fragments are typically <200 bp in length, whereas the DNA that results from cellular damage is >300 bp in length, the skilled artisan performing the analyses of Stone et al would be motivated to perform an analysis including quantifying long or short nucleic acid fragments to identify the portion of any cell-free DNA in a perfusate that are indicative of cell-death related to apoptosis and thus indicative of a potentially less successful graft transplant.
Relevant to the fragment length limitations of claim 37, the prior art of Norton et al teaches that apoptosis-derived fragments are shorter than the DNA that results from damage of cells. Norton et al also teaches the analysis of particularly sized amplicons to address amplification efficiency and variability in quantitative PCR systems (e.g.: p.1561). Thus in regard to the limitations of the claims, where apoptotic derived cf-DNA is taught in the prior art as less than 200bp in length, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp for optimization of the method. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. It would have been prima facie obvious to one of ordinary skill in the art before the effective filling date of the methods of the instantly rejected claims to have detected cf-DNA of the required size for the detection of apoptosis-derived nucleic acids and cell-lysis derived nucleic acids.
Claim(s) 45 is/are rejected under 35 U.S.C. 103 as being unpatentable over Stone et al (2016) (citation 23 on the IDS of 07/17/2026) in view of Van Raemdonck et al (2014) (citation 23 on the IDS of 07/17/2026), Snyder et al (2011) (citation 21 on the IDS of 07/17/2026), Goncalves-Primo et al (2014) (citation 5 on the IDS of 07/17/2026) and Norton et al (2013) (citation 14 on the IDS of 07/17/2026), as applied to claims 36-44 and 46-50 above, and further in view of Olerup et al (1992) (citation 16 on the IDS of 07/17/2026).
Stone et al in view of Van Raemdonck et al, Snyder et al Goncalves-Primo et al and Norton et al and renders obvious the method of claim 36, as detailed above. Stone et al in view of Van Raemdonck et al, Snyder et al Goncalves-Primo et al and Norton et al does not specifically provide for a cfDNA detection that comprises performing mismatch PCR.
Olerup et al teaches the use of PCR that includes the use of primers with a deliberate mismatch to detect specific nucleic acid sequences (e.g.: p.233, right col), as well as mismatches that do not amplify non-target sequences (e.g.: p.234, left col).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date the instantly rejected claims to have applied the mismatch PCR techniques of Olerup et al in the perfusate sample analysis rendered obvious by Stone et al in view of Van Raemdonck et al, Snyder et al Goncalves-Primo et al and Norton et al. The skilled artisan would be motivated to use the mismatch PCR of Olerup et al based on the expressed teachings of Olerup et al that the method can accurately and efficiently detect specific target nucleic acid sequence (where the perfusate sample rendered obvious by the prior art may contain cfDNA of donor graft origin as well as from added red blood cells as taught by Van Raemdonck et al), and the teaching of Stone et al that DNA released from the donor organ is suggestive of cell death in the donor organ.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 36-50 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 12,084,720. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the conflicting patent include the same analyses and methodological steps performed on the same samples as claimed in the methods of the rejected claims.
Conclusion
No claim is allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Khoja et al (US PG Pub 20170283788) teaches (e.g.: para 0024) different lengths of nucleic acid fragments that are produced via apoptosis versus cell lysis.
Seligson et al (US PG Pub 20150211070) teaches (e.g.: para 0042-0045) different lengths of nucleic acid fragments that are produced via apoptosis versus cell lysis.
Steen et al (2003) provides a teaching that red blood cells added to perfusion solution in the Lund protocol are obtained from separate animals.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
