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
Summary
This is Final Office action based on the 18/012054 RCE response filed on 09/18/2026.
Claims 4, 8, 11, 14-15, 59-66 have been fully considered and examined.
Claims 1-3, 5-7, 9-10, 12-13, 16-58, & 67 have been cancelled.
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.
Claim(s) 4, 8, 11, 14-15, & 59-66 is/are rejected under 35 U.S.C. 103 as being unpatentable over GEOPRGE in WO 2019079743 (as cited on IDS 01/18/2024) in view of SEHGAL in US 20120028236.
With respect to Claim 4, GEOPRGE teaches of a composition (abstract) which is used in/ with a sample collection tube for blood, and the composition can contain acid citrate dextrose (ACD) as an anticoagulant (paragraph 0057, 0069). The composition in addition to the anticoagulant (ACD), includes and cyclodextrin (paragraph 0016) and the cyclodextrin can be alpha-cyclodextrin (paragraph 0017) and imidazolidinyl urea (paragraph 0009).
GEOPRGE further teaches of contacting a blood sample comprising proteins with the composition in a blood sample collection tube and isolating a fraction containing the proteins (paragraph 0014, 0102, 0101, 0038, 0106) which provides a stabilized sample for proteomic analysis (paragraph 0038).
GEOPRGE even further teaches that the composition can be used to stabilize platelets (paragraph 0046).
GEOPRGE does not teach of the use of verapamil (calcium channel blocker) in the composition.
SEHGAL is used to remedy this. SEHGAL specifically teaches of a platelet preservation composition that contains an anticoagulant, and also an inhibitor of platelet activation(abstract). SEHGAL further teaches of the platelet activation inhibitors including one or more messenger effectors including calcium channel blockers (paragraph 0038). Specifically, SEHGAL teach of the calcium channel blocker being felodipine, isradipine, nicardipine, or verapamil hydrochloride (paragraph 0039).
GEOPRGE and SEHGAL are analogous art, and both teach their compositions can be used for platelet stabilization and preservation and therefore there would have been reasonable expectation of success. It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention and one would have had reasonable expectation of success of/to include a calcium channel blocker or calcium sequestering agents (verapamil hydrochloride) as is done in SEHGAL in the stabilization compound of GEOPRGE due to the advantages calcium channel blockers offer in protecting platelets during storage and increasing shelf-life due to the specific difficulty known with storing platelets as compared to just regular blood cells and the need for improvement thereon (SEHGAL, paragraph 0007, 0034, 0018, 0005).
With respect to Claims 8, GEOPRGE teaches of a composition (abstract) which is used in/ with a sample collection tube for blood, and the composition can contain acid citrate dextrose (ACD) as an anticoagulant (paragraph 0057, 0069). The composition in addition to the anticoagulant (ACD), includes and cyclodextrin (paragraph 0016) and the cyclodextrin can be alpha-cyclodextrin (which can be considered a red blood cell stabilizer) (paragraph 0017).
With respect to Claim 11, GEOPRGE teaches the molarity of the citrate utilized for the compositions herein is preferably from about 0.05 M to about 0.2 M and that it is concentrated for 8.5 or 6 milliliters of blood.
For .2M in 6 milliliters of blood this works out to 78.8 g/L, which falls in the claimed range. The examiner notes the term “about,” so that even if the concentration fell outside of the claimed range, it could still broadly read on the claim.
Further, it would have been obvious to one of ordinary skill in the art to adjust the concentrations into this desired range through routine optimization. See MPEP 2144.05- routine optimization & overlapping, approaching, and similar ranges, amounts and proportions.
With respect to Claim 14, GEOPRGE teaches of using imidazolidinyl urea, the aldehyde releasing agent, in a concentration of 10 to 40 % (paragraph 0017, 0009, 0109).
Though GEOPRGE does not call out the exact claimed concentration range of 0.1 g/ml to 3 g/l of anticoagulant, it shows the ability to adjust and the concentration parameters and interchange composition ingredients (paragraphs 0109, 0017). It would have been obvious to one of ordinary skill in the art to adjust the concentrations into this desired range through routine optimization. See MPEP 2144.05- routine optimization & overlapping, approaching, and similar ranges, amounts and proportions.
With respect to Claim 15, GEOPRGE teaches teach of the composition containing an amine (paragraph 0008).
With respect to Claim 59, GEOPRGE teaches of a method of making a composition and preparing sample for analysis (abstract) which is used in/ with a sample collection tube for blood, and the composition can contain acid citrate dextrose (ACD) as an anticoagulant (paragraph 0057, 0069). The composition in addition to the anticoagulant (ACD), includes and cyclodextrin (paragraph 0016) and the cyclodextrin can be alpha-cyclodextrin (paragraph 0017) and imidazolidinyl urea (paragraph 0009).
GEOPRGE further teaches of contacting a blood sample comprising proteins with the composition in a blood sample collection tube and isolating a fraction containing the proteins (paragraph 0014, 0102, 0101, 0038, 0106) which provides a stabilized sample for proteomic analysis (paragraph 0038).
GEOPRGE even further teaches that the composition can be used to stabilize platelets (paragraph 0046).
GEOPRGE does not teach of the use of verapamil (calcium channel blocker) in the composition.
SEHGAL is used to remedy this. SEHGAL specifically teaches of a platelet preservation composition that contains an anticoagulant, and also an inhibitor of platelet activation(abstract). SEHGAL further teaches of the platelet activation inhibitors including one or more messenger effectors including calcium channel blockers (paragraph 0038). Specifically, SEHGAL teach of the calcium channel blocker being felodipine, isradipine, nicardipine, or verapamil hydrochloride (paragraph 0039).
GEOPRGE and SEHGAL are analogous art, and both teach their compositions can be used for platelet stabilization and preservation. It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention and one would have had reasonable expectation of success of/to include a calcium channel blocker or calcium sequestering agents (verapamil hydrochloride) as is done in SEHGAL in the stabilization compound of GEOPRGE due to the advantages calcium channel blockers offer in protecting platelets during storage and increasing shelf-life due to the specific difficulty known with storing platelets as compared to just regular blood cells and the need for improvement thereon (SEHGAL, paragraph 0007, 0034, 0018, 0005).
With respect to Claim 60, GEOPRGE further teaches of contacting a blood sample comprising proteins with the composition in a blood sample collection tube and isolating a fraction containing the proteins (paragraph 0014, 0102, 0101, 0038, 0106) which provides a stabilized sample for proteomic analysis (paragraph 0038), and analysis of peptides (paragraph 0069).
With respect to Claim 61, GEOPRGE teaches that the fraction can be a plasma fraction of a cellular fraction (paragraph 0006).
With respect to Claim 62, GEOPRGE teaches of lysing after 4 days (paragraph 0020, 0022).
With respect to Claim 63, GEOPRGE teaches that the cells can be fragile cells including circulating tumor cells (paragraph 0012, 0033).
With respect to Claim 64, GEOPRGE teaches of a method for using a composition to prepare and analyze a sample (abstract) which is used in/ with a sample collection tube for blood, and the composition can contain acid citrate dextrose (ACD) as an anticoagulant (paragraph 0057, 0069). The composition in addition to the anticoagulant (ACD), includes and cyclodextrin (paragraph 0016) and the cyclodextrin can be alpha-cyclodextrin (paragraph 0017) and imidazolidinyl urea (paragraph 0009).
GEOPRGE further teaches of contacting a blood sample comprising proteins with the composition in a blood sample collection tube and isolating a fraction containing the proteins (paragraph 0014, 0102, 0101, 0038, 0106) which provides a stabilized sample for proteomic analysis (paragraph 0038).
GEOPRGE even further teaches that the composition can be used to stabilize platelets (paragraph 0046).
GEOPRGE further teaches of contacting a blood sample comprising proteins with the composition in a blood sample collection tube and isolating a fraction containing the proteins (paragraph 0014, 0102, 0101, 0038, 0106) which provides a stabilized sample for proteomic analysis (paragraph 0038), and analysis of peptides (paragraph 0069).
GEOPRGE further teaches of using the composition for mass spectrometry analysis (paragraph 0102) and teaches that the composition only “may include,” enzyme inhibitors, which means that it also may not include enzyme inhibitors, as claimed.
GEOPRGE does not teach of the use of verapamil (calcium channel blocker) in the composition.
SEHGAL is used to remedy this. SEHGAL specifically teaches of a platelet preservation composition that contains an anticoagulant, and also an inhibitor of platelet activation(abstract). SEHGAL further teaches of the platelet activation inhibitors including one or more messenger effectors including calcium channel blockers (paragraph 0038). Specifically, SEHGAL teach of the calcium channel blocker being felodipine, isradipine, nicardipine, or verapamil hydrochloride (paragraph 0039).
GEOPRGE and SEHGAL are analogous art, and both teach their compositions can be used for platelet stabilization and preservation. It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention and one would have had reasonable expectation of success of/to include a calcium channel blocker or calcium sequestering agents (verapamil hydrochloride) as is done in SEHGAL in the stabilization compound of GEOPRGE due to the advantages calcium channel blockers offer in protecting platelets during storage and increasing shelf-life due to the specific difficulty known with storing platelets as compared to just regular blood cells and the need for improvement thereon (SEHGAL, paragraph 0007, 0034, 0018, 0005).
With respect to Claim 65, GEOPRGE teaches that that composition of the instant invention is stored with the sample for at least 2 days, which is 48 hours (paragraph 0020).
With respect to Claim 66, GEOPRGE that the sample stability/ the sample storing can be from about 4 degrees Celsius to about 50 degrees Celsius (paragraph 0011).
Response to Arguments and Declaration
Applicant's arguments filed 09/18/2026 have been fully considered but they are not persuasive. A Declaration by Bradford A. Hunsley was also submitted dated 09/18/2026. Both of these documents were reviewed and were not found convincing in overcoming the prior art rejections for the broadly claimed composition and method of analysis and preparation of a protein sample using this composition. No amendments were made in response dated 09/18/2026, however applicant’s arguments in both the arguments and Declaration are responded to below.
Applicant argues that one would not choose or be motivated to select/choose specifically verapamil from the multitude of compounds/laundry list disclosed in SEHGAL, paragraph 0039, since it is not identified as a “preferred,” compound and one would not have reasonable success in combining it with GEOPRGE, since SEHGAL teaches of using verapamil only as an optional component.
The examiner disagrees, and maintains that one of ordinary skill in the art would have been motivated to choose any of the compounds in SEHGAL, including verapamil, paragraph 0039 (which are listed as optional to each other) to help as a second messenger effector or calcium sequestering agent or calcium channel blocker as this is what all the compounds in SEHGAL paragraph 0039 are labeled as, and would in fact have reasonable expectation of success, since these inhibit platelet activation (and therefore allow them to be stored longer). SEHGAL teaches that a list of compounds work for this purpose, so it would have been obvious to choose any of them, especially in a composition for platelet stabilization and preservation—which both the GEOPRGE and SEHGHAL references focus is on.
Applicant further argues that since SEHGAL lists anticoagulant citrate dextrose (ACD) first in its list of calcium sequestering agents one would chosen ACD and not verapamil which is later in the list if looking to add a calcium sequestering agent. The examiner disagrees with this and notes that this is a matter of applicant’s opinion. There is appropriate reason for combination as shown above.
Applicant further argues that since the composition taught in GEOPRGE already uses ACD, which is also listed in the paragraph 0039 list of SEHGAL, that one would not be motivated to use verapamil in addition to the ACD. The examiner disagrees as SEHGHAL teaches that any combination of second messenger effectors (which include the calcium sequestering agents of paragraph 0039) can be used (Claim 7).
Applicant argues more specifically that the combination of GEOPRGE and SEHGHAL do not show reasonable expectation that the composition would improve stabilization of blood cells or associated analytes nor does the combination produce the “unexpectedly improved properties exhibited by the claimed composition including platelet preservation, red blood cell stabilization, white blood cell stabilization, plasma protein preservation, and suppression of platelet activation.” The examiner disagrees, and notes that these limitations are not unexpected properties, but instead are intended use for the claimed composition. Further—as shown already, SEHGAL does in fact show a composition useful in platelet preservation and stabilization, and wherein verapamil can be used in it as a calcium channel blocker.
Applicant also argues with respect to the Hunsley Declaration submitted 09/18/2026, that it demonstrates that prior to the effective filing date of the instant invention verapamil increased fragility and promoted hemolysis and thus a skilled artisan would have had reason to believe that inclusion of the verapamil could negatively impact RBC stability and would not have been used in a stabilization/preservation composition. While the examiner does see this from the reference/experimental results Dr. Hunsley cites, the examiner maintains that the SEHGAL reference teaches differently—and again does in fact teach of using verapamil (paragraph 0039) in a composition for stabilizing and preserving platelets (abstract). Citation of a negative teaching does not negate what is taught in fact by the cited prior art of GEOPRGE in view of SEHGAL.
Therefore, in contrast to what applicant argues--- the examiner maintains that the office has in fact satisfied MPEP 2143 and has shown rational underpinning and a level of predictability to support the obviousness rejection.
Applicant further argues that the claimed selection of verapamil in the claimed composition was not routine. The examiner is confused by the statement of this argument, but overall what applicant seems to be arguing here is that applicant thinks the calcium sequestering agents taught in SEHGAL would not behave similarly when incorporated into the composition of GEOPRGE. Applicant argues that the data in the Declaration show that verapamil outperforms other tested calcium channel blockers, and for this reason one wouldn’t have routinely selected verapamil. Though the examiner does admit, that SEHGAL does not specifically teach of verapamil having superior abilities to the other calcium channel blockers/sequestering agents in paragraph 0039 of SEHGAL, the examiner maintains that it does not have to, and no superior material properties of the overall composition is claimed. Further, what applicant seems to argue that the superior properties are, is platelet stability and preservation, which again--- both GEOPRGE and SEHGAL do in fact teach of. Therefore, applicant’s argument is not convincing.
Applicant further argues that the objective evidence demonstrates that the Office has not established a prima facie case of obviousness. The examiner disagrees. Applicant argues to this point that the prior art does not show the “unexpectedly improved stabilization across multiple biological systems.” Again, with respect to this--- the examiner notes that this is intended use for the claimed composition, and none of this is claimed. Further--- the examiner notes that there is adequate reason for combination of the references and therefore therefore a prima facie case of obviousness is established.
Applicant seems to focus arguments on that they think verapamil shows a much improved/superior stabilization affect in the preservation/stabilization composition. The examiner maintains that SEHGAL teaches of using verapamil in a stabilization/preservation of platelet composition. Therefore, the claimed composition would not in fact be superior to a composition which already has verapamil in in (SEHGAL).
Therefore, the claim rejections are maintained. And, though the examiner found Dr. Hunsleys Declaration informative, it and arguments dated 09/18/2026 are not found convincing.
All claims remain rejected.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
DENG in US 20110027771 teaches of compositions and methods for stabilization, enrichment, and analysis of fragile cells(abstract). DENG teach that the sample is a blood sample and that the stabilization compound is contacted with the blood sample (paragraphs 0022-0025). DENG further teach of isolating a sample suitable for analysis (paragraph 0003, 0004,0109, 0125, 0199,0200), analyzing the cellular components to diagnose condition (paragraph 0023) and proteins can be detected or identified with the instant composition (paragraph 0230, paragraph 0261-0264). DENG further teach that mass spectrometry or tandem mass spectrometry can be used with the instant method and composition (paragraph 0240).
DENG further teach of adding the stabilization composition to a tube with a blood sample of which the amount of sample can vary (blood collection tube) (paragraphs 0031-0032, 0114-0118, 0128 & 0150), and that the composition can contain anticoagulants (paragraph 0005, 0013) and antiplatelet drugs (compound that inhibits platelet activation) (paragraph 0011).
DENG teaches of using citrate dextrose or acid citrate dextrose in the composition (paragraph 0077). DENG further teaches that the stabilizing composition can include imidazolidinyl urea or diazolidinyl urea (which are aldehyde releasers), along with the sodium citrate, mM adenosine, theophylline, and dipyridamole (paragraph 0271, Table 2, composition B). DENG teaches that the sodium citrate can instead of citric acid (paragraph 0077).
DENG does not teach of the use of verapamil.
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 REBECCA M FRITCHMAN whose telephone number is (303)297-4344. The examiner can normally be reached 9:30-4:30 MT Monday-Friday.
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/REBECCA M FRITCHMAN/Primary Examiner, Art Unit 1758
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