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 Amendment
Applicant's amendment and argument filed 07/16/2025, in response to the non-final rejection, are acknowledged and have been fully considered. Any previous rejection or objection not mentioned herein is withdrawn.
Claims 1-12, 15, 17, 19-20, 22, 24-29 and 36-37 are pending of which claims 9-10, 26-29 and 31-33 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/24/2022.
Claims 1-7, 11-12, 15, 17, 19-20, 22, 24-25 and 36-37 are being examined on the merits.
Claim Rejections - 35 USC § 102
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 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, 3-4 and 7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jeanette M. van den Goor et. al. (From IDS, Cell Saver device efficiently removes cell-derived microparticles during cardiac surgery, Journal of Thoracic and Cardiovascular Surgery, Feb 24, 2007; Vol 134, No: 3, 799-801), herein after van den Goor. This rejection is maintained with slight modifications due to the arguments filed on 07/16/2025.
Van den Goor discloses removing of red cell-derived microparticles by use of the Cell Saver device. The Cell Saver device concentrates erythrocytes and discards plasma. Van den Goor discloses removing platelet-derived and erythrocyte-derived microparticles (see 799, left column). Thus removing the blood and plasma from a subject to concentrate erythrocytes and removing the microparticles from the removed blood and plasma would ultimately be the same as removing red-cell derived particles from plasma isolated from a subject as being claimed.
Regarding claim 7, van den Goor discloses wherein the cell derived microparticles are on average in a size ranging from 100 nm to 1.0 um.
Claims 1-5 and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Johansen et. al. (From IDS, Exchange Plasmapheresis is Effective in Removing Procoagulation Microparticles and Has Additional Therapeutics Benefit in the Treatment of TTP, Blood (2013) 122 (21): 3584), hereinafter Johansen. This rejection is maintained with slight modifications due to the arguments filed on 07/16/2025.
Regarding claims 1-5 and 15, Johnasen discloses wherein patients presenting with acute thrombocytopenic purpura (TTP) were admitted for exchange plasmapheresis wherein microparticles from red cells were removed and analyzed (see abstract: methods). Johansen discloses that the trend in the analysis indicated that the plasmapheresis reduced procoagulance and hypercoagulability. It would be appreciated and known by those having ordinary skill in the art that plasmapheresis uses centrifugation and filtration as a process to remove red blood cells from plasma to replace back into the subject having the process done. Here Johansen also discloses the removal of microparticles from red blood cells (erythrocytes). Thus removing the blood and plasma from a subject and removing the microparticles from the removed blood and plasma would ultimately be the same as removing red-cell derived particles from plasma isolated from a subject as being claimed.
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 1-5, 7, 9-12, 15, 17, 19-20, 24-25, 37 are rejected under 35 U.S.C. 103 as being unpatentable over Johasen (From IDS, Exchange Plasmapheresis is Effective in Removing Procoagulation Microparticles and Has Additional Therapeutics Benefit in the Treatment of TTP, Blood (2013) 122 (21): 3584), hereinafter Johansen, Grisendi et. al. (Detection of microparticles from human red blood cells by multiparametric flow cytometry, Blood Transfus 2015; 13: 274-280), Paul Simon and Scott Dessain (WO2012158195A2) hereinafter Simon. This rejection is maintained with slight modifications due to the arguments filed on 07/16/2025.
Johnasen discloses wherein patients presenting with acute thrombocytopenic purpura (TTP) were admitted for exchange plasmapheresis wherein microparticles from red cells were removed and analyzed (see abstract: methods). Johansen discloses that the trend in the analysis indicated that the plasmapheresis reduced procoagulance and hypercoagulability. It would be appreciated and known by those having ordinary skill in the art that plasmapheresis uses centrifugation and filtration as a process to remove red blood cells from plasma to replace back into the subject having the process done. Here Johansen also discloses the removal of microparticles from red blood cells (erythrocytes).
Johansen does not specifically teach removing of particles with GPA on the surface.
Grisendi’s general disclosure is a report on the detection of microparticles from human red blood cells through flow cytometry (see abstract: background).
Grisendi teaches “It has been established that RBC microparticles can be identified by flow cytometry thanks to their expression of glycophorin A, a protein uniquely expressed by erythrocytes, and phosphatidylserine (PS). Phosphatidylserine is normally exposed on the inner leaflet of the cell membrane; however, during apoptosis it is exposed on the outer side of the membrane, becoming detectable by annexin” (see page 275, left column 2nd para.).
Grisendi teaches “Microparticles are small phospholipid vesicles of less than 1 µm in size, containing a subset of proteins derived from their parent cells” (see page 274, right column) and teaches wherein sizes of MPs were detected using side scatter 0.5 um beads FSC size range, and indeed show overlapping ranges of the instantly claimed (see Figure 1).
Simon’s general disclosure is to clearing pathogen and toxins, through the use of ligands targeting circulating non-lymphoid cells linked to an agent to bind toxins (see abstract).
Simon teaches “The present invention is based, in part, on our discovery that methods that enhance the immune-adherence of antibodies to red blood cells may be useful for prophylaxis and treatment of BoNT and other toxic substances or pathogens. Antibody immune-adherence may be enhanced using a fusion protein (FP), a recombinant protein that links an scFv derived from a monoclonal antibody specific for glycophorin A, the prevalent RBC surface protein, to streptavidin. We have found that the FP significantly augmented the neutralizing capability of these antibodies in vivo” (see Summary, page 2, first para.).
“Red blood cells express a distinctive complement of cell surface markers, including the human blood group antigens, glycophorins, band 3 and the Lewis antigens. Glycophorin A (GPA) is exclusively expressed on erythroid cells and in the blood by RBCs. No other circulating cells are known to express GPA” (see page 6, lines 22-25). Simon teaches creating polymer based-fusion proteins for removing GPA.
“One example of a polymer-based fusion protein can be the addition of equimolar amounts of a ligand (e.g., an anti-glycophorin A monoclonal antibody) and biotin-binding protein (e.g., streptavidin) to produce a complex with a co-polymeric scaffold studded with targeting antibody molecules as well as biotin-binding molecules” (see page 32-33, lines 29-30 and lines 1-2).
“Ligands may be screened against known related target polypeptides to isolate a ligand
that specifically binds the target. For example, a ligand specific to a target will flow through an
affinity chromatography column comprising other closely related target molecules adhered to
insoluble matrix under appropriate buffer conditions. Such screening allows isolation of ligands
non-cross reactive to closely related targets (Antibodies: A Laboratory Manual, Harlow and Lane
(eds.), Cold Spring Harbor Laboratory Press, 1988; Current Protocols in Immunology, Cooligan
et al. (eds.), National Institutes of Health, John Wiley and Sons, Inc., 1995). Screening and
isolation of specific antibodies is well known in the art (see, Fundamental Immunology, W. Paul
(ed.), Raven Press, 1993; Getzoff et al., Adv. In Immunol. 43: 1-98, 1988; Monoclonal Antibodies: Principles and Practice, Goding, J. W. (ed.), Academic Press Ltd., 1996; Benjamin et
al., Ann. Rev. Immunol. 2: 67-101, 1984)” (see page 10, lines 1-11). Here Simon teaches using affinity chromatography for targeting GPA.
Regarding claims 20 and 37, pertaining to wherein the modified plasma has a clotting time approximately the same as the clotting time for control plasma from a healthy donor or at least two times longer or increased two-fold relative to the plasma, these outcomes would be inherent to the process as the process are the same, unless given evidence to the contrary by the applicant. Additionally, since the Office does not have the facilities for examining and comparing applicants’ composition with the composition of the prior art, the burden is on applicant to show a novel or unobvious difference between the claimed product and the product of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980), and “as a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith.” In re Brown, 459 F.2d 531, 535, 173 USPQ 685, 688 (CCPA 1972).
Therefore it would have been obvious to persons having ordinary skill in the art, before the effective filing date to target glycophorin A (GPA), using anti-GPA molecules when trying to remove red cell-derived microparticles from fresh plasma because as Grisendi teaches this marker is found on the surface of RDCPs. Simon teaches one of ordinary skill could use monoclonal antibodies targeting GPA and use affinity chromatography as a means in targeting and removing the components expressing this marker.
It would have also been obvious to include the particles within the instantly claimed range because Grisendi teaches particles within this range. Using filters within a particular size range that would allow for the particles to pass or be excluded are also obvious given that the art teaches particular size ranges which constitute those particles and teaches the use of FLOW cytometry which also filters components based on size. Removing 90% or more of the red cell-derived particles would have been obvious because these components are what is taught to be removed from the plasma and thus having a 90% removal rate would have been completely obvious.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over (From IDS, Exchange Plasmapheresis is Effective in Removing Procoagulation Microparticles and Has Additional Therapeutics Benefit in the Treatment of TTP, Blood (2013) 122 (21): 3584), hereinafter Johansen, Grisendi et. al. (Detection of microparticles from human red blood cells by multiparametric flow cytometry, Blood Transfus 2015; 13: 274-280), Paul Simon and Scott Dessain (WO2012158195A2) hereinafter Simon as applied to claims 1-5, 7, 9-12, 15, 17, 19-20, 24-25, 37 above, and further in view of Olatunya et. al. (Red blood cells microparticles are associated with hemolysis markers and may contribute to clinical events among sickle cell disease patients, Annals of Hematology (2019) 98: 2507-2521). This rejection is maintained with slight modifications due to the arguments filed on 07/16/2025.
Johansen, Grisendi and Simon’s combined teachings, teach the instantly claimed method of decreasing hypercoagulability however are silent on wherein the plasma is isolated from a subject with a hemoglobinopathy.
Olatunya’s general disclosure is a report about red blood cell microparticles being associated with hemolysis markers in sickle cell disease (SCD) (see abstract).
Olatunya teaches that microparticles are sub-micron vesicles possessing protein and other materials derived from the plasma membrane of their parent cells, and literature suggests that they may play a role in the pathophysiology and downstream manifestations of sickle cell disease (SCD).
Furthermore, the generated red blood cells microparticles (RMP) has been speculated to be able to contribute to the vascular, oxidative, and inflammatory lesions and other complications of SCD.
“We suspect that both RMP and heme perhaps mediate and promote leg ulceration through their oxidative injuries and possible NO depletion upon their release as demonstrated by Camus and colleagues [17]. The observations by Camus and colleagues were also earlier corroborated by Liu et al. [33], as they demonstrated that, through a concentration-dependent gradient, RMPs are capable of entering significantly into the free zone of vasculature from where they can interact with endothelial cell lining of blood vessels and mediate NO depletion thereby causing vascular damages and other injuries. Drawing from these, it is therefore possible that the association of both the RMP and heme with leg ulcer among the patients in this study could be as a result of injuries from NO depletion, oxidative stress, and other mediatory molecules causing both vascular and cellular damages to these patients. This further points to the possible contributions of RMP to the pathophysiology of SCD through hemolysis and possible endothelial cell lesions” (see Discussion para. 5).
Therefore, it would have been obvious to persons having skill in the art before the effective filing date to use the treatment taught by Johansen, Grisendi and Simon on sickle cell disease patients because as Olatunya teaches, red blood cell microparticles are associated with pathophysiology and downstream manifestations of sickle cell disease such as vascular, oxidative and inflammatory lesions. Removing the RBCP from patients having sickle cell disease would have been prima facie obvious given the prior art.
Claim 36 is rejected under 35 U.S.C. 103 as being unpatentable over (From IDS, Exchange Plasmapheresis is Effective in Removing Procoagulation Microparticles and Has Additional Therapeutics Benefit in the Treatment of TTP, Blood (2013) 122 (21): 3584), hereinafter Johansen, Grisendi et. al. (Detection of microparticles from human red blood cells by multiparametric flow cytometry, Blood Transfus 2015; 13: 274-280), Paul Simon and Scott Dessain (WO2012158195A2) hereinafter Simon as applied to claims 1-5, 7, 9-12, 15, 17, 19-20, 24-25, 37 above, and further in view of Martin Raber (Clinical Methods: The History, Physical, and Laboratory Examinations, 3rd Edition, Coagulation Tests, Chapter 157, 1990). This rejection is maintained with slight modifications due to the arguments filed on 07/16/2025.
Johansen, Grisendi and Simon’s combined teachings, teach the instantly claimed method of decreasing hypercoagulability however are silent on wherein the plasma is presumably measured using Factor Xa-activated clotting time, the thrombin time, the activated partial thromboplastin time, the prothrombin time, or the activated clotting time.
Raber’s general disclosure is a chapter explaining coagulation tests.
Raber teaches “These in vitro tests—the activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT)—measure the time elapsed from activation of the coagulation cascade (Figure 157.1) at different points to the generation of fibrin” (see Tests of the Coagulation Cascade).
Therefore, it would have been obvious to persons having skill in the art before the effective filing date to use either activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT) as a means for determining clotting time because as Raber teaches, these assays measure clotting time and are commonly used in the art.
There would have been a reasonable expectation of success in arriving at the instant invention because each limitation is known in the art and would have been made obvious given the relied upon pieces of art.
Response to Arguments
Applicant's arguments filed 07/16/2025 have been fully considered but they are not persuasive. The applicant argues many limitations that are not being actually claimed. The applicant argues that Van den Goor relates to the processing of whole blood and not the removal of RCDPs from a subject’s plasma. Van den Goor discloses that the Cell Saver device concentrates erythrocytes and discards plasma and removing platelet-derived and erythrocyte derived microparticles. Even though Van den Goor teaches the starting material is whole blood, the fact that plasma, erythrocytes and red cell derived microparticles are separated out would also indicate removing platelet-derived and erythrocyte derived microparticles from the whole blood and plasma would also separate those from plasma as well. Each of these exist in whole blood together and thus separating out each from each other would ultimately separate out RCDPs from plasma isolated from a subject as instantly claimed. As the applicant admits in their response the art teaches that the whole blood is processed extracorporeal (existing outside the body). This along with the separation process taught in the art would indicate isolation of plasma from a subject and removal of RCDPs from the plasma, even if the art teaches that the starting material was whole blood.
The applicant argues that plasma is “produced” by removing red blood cells such as erythrocytes. This process does not produce plasma. This process separates plasma from erythrocytes.
The applicant argues that Johansen relates to exchange plasmapheresis on microparticle levels in patients with acute thrombocytopenic purpura and that exchange plasmapheresis is the removal and subsequent exchange of blood plasma to the blood circulation. In contrast the applicant compares this to removing RCDPs from a subject’s own plasma (autologous plasmapheresis) as outlined on page 29, lines 11-16 of the instant application. These are limitations that are not being claimed by the applicant and these limitations are not to be read from the applicant’s specifications into the claims even if this is what the applicant tested or discovered. The applicant merely claims isolating from “a subject” and nowhere does the applicant claim there to be an autologous plasmapheresis as being argued.
The applicant argues that an exchange plasmapheresis step should not be conflated with an active step of removing RCDPs from plasma isolated from a subject. The step of removing red blood cells from plasma which also contain microparticles, would ultimately remove those particles from the plasma too.
The applicant argues that the claims are not obvious because each limitation is not taught. This however is not the case as the applicant is arguing limitations that are not being claimed.
The applicant argues that there are some unexpected results. The results being argued are not commensurate in scope with what is being claimed. The applicant is arguing data which pertains to RCDPs derived from sickle cell disease patients. The applicant argues that it is unexpected that removing RCDPs from sickle cell disease patients increases clotting time in both healthy individuals and sickle cell patients. The art recognizes that removing RCDPs would indeed have this effect. Both Johansen and Van de Goor teach that this would be expected and Olatunya teaches these particles from sickle cell patients may play a role in pathophysiology and downstream manifestations of sickle cell disease. Thus removing the RCDPs from sickle cell patients would have been prima facie obvious given the art.
The applicant argues that Gisendi does not teach microparticles being formed in vivo (e.g. diseased patients). Only teaches breakdown of samples during storage ex vivo. Grisendi is relied upon to show that microparticles from human red blood cell contain the marker GPA on the surface and that flow cytometry can be used to confirm and identify this along with a means for separating. These are commonly used techniques in the field and known to those skilled in the art. This teaching relied upon would make obvious using the marker GPA which is known to be found on RCDPs as discussed by Grisendi for isolating RCDPs from plasma, because the process of flow cytometry exploits the use of surface markers on cells and particles which can be captured by antibodies that are attracted to those markers and separated through the use of the cytometer’s sorting process.
The applicant is arguing that Simon’s invention is not the same as what is being claimed. The Office does not make this assertion. The Office relies on Simon to show how one can rely on the use of monoclonal antibodies and affinity chromatography as a means for targeting and removing the components expressing the GPA molecules. The applicant argues that Simon teaches away form ex vivo treatment. This is not the case. Simon is not being relied upon for the entire scope of their teachings but merely for making obvious specific uses of using GPA as a target molecule which can be exploited by monoclonal antibodies for affinity chromatography and Grisendi teaches that these same GPA molecules are found on the RCDPs thus making obvious the removal of those RCDPs with the use of affinity chromatography by targeting the GPA with monoclonal antibodies.
The applicant argues that Olatunya does not teach removal of RCDPs from plasma. The teaching that the removal of the RCDPs has already been disclosed for decreasing hypercoagulability and/or increasing clotting time. Olatunya is relied upon to teach that these particles may play a role in pathophysiology and downstream manifestations of sickle cell thus persons having skill in the art and given the relied upon art would want to use the treatment on sickle cell patients in order to reduce or eliminate the downstream manifestations and pathophysiology. The applicant argues that sickle leg ulcer and TRV are not associated with hypercoagulability. Sickle leg ulcers indeed are often linked to a hypercoagulable state.
The applicant argues that Olatunya does not show any link between the RMPs and sickle cell disease. Olatunya teaches specifically that the generated RMP has been speculated to be able to contribute to the vascular, oxidative, and inflammatory lesions and other complications of sickle cell disease. Olatunya teaches that both RMP and heme perhaps mediate and promote leg ulceration through their oxidative injuries and possible NO depletion upon their release as demonstrated by Camus and colleagues. The observations by Camus and colleagues were also earlier corroborated by Liu et al., as they demonstrated that, through a concentration-dependent gradient, RMPs are capable of entering significantly into the free zone of vasculature from where they can interact with endothelial cell lining of blood vessels and mediate NO depletion thereby causing vascular damages and other injuries. Drawing from these, it is therefore possible that the association of both the RMP and heme with leg ulcer among the patients in this study could be as a result of injuries from NO depletion, oxidative stress, and other mediatory molecules causing both vascular and cellular damages to these patients. This further points to the possible contributions of RMP to the pathophysiology of SCD through hemolysis and possible endothelial cell lesions. Therefore because of their contribution to lesions, oxidative stress and vascular damage, these reasons make obvious to remove RMPs or RCDPs from sickle cell patients.
The applicant argues that Raber does not disclose the impact of RCDPs on hypercoagulability. Raber’s disclosure is relied upon to teach using activated partial thromboplastin time, prothrombin time and thrombin time as methods of determining clotting time as instantly claimed and recognized by the prior art. Raber is not being relied upon to anticipate the instant base claim as being argued.
Conclusion
Currently no claims are allowed.
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 JACOB ANDREW BOECKELMAN whose telephone number is (571)272-0043. The examiner can normally be reached Monday-Friday 8am-5pm.
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JACOB A BOECKELMANExaminer, Art Unit 1655
/TERRY A MCKELVEY/Supervisory Patent Examiner, Art Unit 1655