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 .
Priority
Priority to US 63/074,751, filed 9/4/2020, is acknowledged.
Claim Status
Claims 8, 11, 12, and 14-29 are pending. Claims 8, 11, 12, and 14-29 are under examination. Claims 25-29 are new.
New Claim Objections
Claims 25 and 26 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Previous Claim Rejections - 35 USC § 112
Claim 20 was previously rejected: the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Response to Arguments
Applicant’s arguments, see Applicant Reply, page 5, para. 7, filed 6/10/2026, with respect to claim 20 have been fully considered and are persuasive. The rejection of claim 20 has been withdrawn.
Maintained 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 8, 11, 15-16, 23, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Palmer et al. (US 20120046231, published 2/23/2012) in view of Su (Su, Jin Bo. World journal of cardiology 7.11: 719 (2015)), Zhang et al. (Zhang, et al. Matrix Biology 71: 421-431 (2018)), and Ostrowski et al. (Ostrowski, et al. Critical care 19.1: 191 (2015)).
Regarding claim 8, claim 8 recites a method of treating endothelial dysfunction in a subject, the method comprising: administering to the subject a therapeutically effective amount of PolyHSA to reduce circulating levels of a biomarker for endothelial dysfunction in the subject.
Palmer et al. discloses administration of PolyHSA as a plasma expander: “In use, PolyHSA is utilized as a plasma replacement composition such as a PE to restore the capacity of the circulatory system to perfuse tissues during a hypovolemic crisis without the substantial side effects that can result from other PE compositions. For this use, a PolyHSA composition is infused into the circulatory system of the subject in a volume sufficient to restore the capacity of the circulatory system to perfuse tissues during a hypovolemic crisis, such as through intravenous or intraarterial infusion through a catheter.: (Palmer et al. para. [0023]).
Palmer does not specifically disclose the treatment of endothelial dysfunction or the lowering of biomarkers for endothelial dysfunction.
However, Su discloses that a major cause endothelial dysfunction is lack of nitric oxide (NO) availability: “Endothelial dysfunction occurs in many cardiovascular diseases, which involves different mechanisms, depending on specific risk factors affecting the disease. Among these mechanisms, a reduction in nitric oxide (NO) bioavailability plays a central role in the development of endothelial dysfunction because NO exerts diverse physiological actions, including vasodilation, anti-inflammation, antiplatelet, antiproliferation and antimigration.” (Su, page 719, Abstract).
Palmer discloses that blood viscosity can activate the synthesis of NO: “Blood viscosity is an important factor that regulates the responses of the cardiovascular system, as it affects shear stress and activates the synthesis of vascular relaxation mediators such as nitric oxide (NO). NO is a critical regulator of basal blood vessel tone and vascular homeostasis, anti-platelet activity, modulation of endothelial and smooth muscle proliferation, and adhesion molecule expression.” (Palmer et al., para. [0007].)
Palmer also discloses the relationship between blood viscosity and NO production: “It has been erroneously perceived that lowering blood viscosity leads to an overall health benefit by decreasing peripheral vascular resistance and heart workload. On the contrary, plasma replacement compositions with a high viscosity increase the blood vessel wall shear stress, which induces endothelial cells to produce NO that dilates the blood vessels. Therefore, vascular resistance and heart workload may be decreased in patients with low Hct or blood volume via a high viscosity plasma replacement composition. The viscosity of a plasma replacement composition can be increased by increasing its MW or concentration or a combination of both.” (Palmer et al., para. [0041]).
Palmer et al. discloses that PolyHSA solutions are high viscosity: “The viscosities of all PolyHSA solutions are higher than the viscosity of HSA at the same total protein concentration. This effect is likely due to the large increase in the weight averaged MW of the PolyHSA solutions, which increases the frequency of molecular interactions between neighboring PolyHSA molecules in solution and increases the solution viscosity.” (Palmer et al., para. [0039]).
Regarding the biomarker, Zhang et al. discloses that glycocalyx is impaired in endothelial cell dysfunction: “Dysfunctional endothelial cells are an essential contributor to the progression of diverse chronic cardiovascular, renal, and metabolic diseases. It manifests in impairment of nitric oxide-dependent vasorelaxation, vascular permeability, and leukocytes deterrent. While endothelial glycocalyx is known to regulate these functions, glycocalyx has been shown to be impaired in pathologic settings leading to endothelial dysfunction.” (Zhang et al., page 421, Abstract). Zhang discloses that these two phenomena are linked: “In summary, we have systematically sketched the components of endothelial mechanotransduction machinery, structure-functional features of endothelial glycocalyx, and pathways of its degradation. Notably, we did not intend to provide a comprehensive review on the subject of endothelial glycocalyx, which has seen many excellent reviews, rather our goal was to present the concept linking dysfunctional endothelium and glycocalyx in a vicious circle.” (Zhang et al., page 428, col. 2, para. 2).
Finally, Ostrowski et al. discloses that circulating synedcan-1 is evidence of glycocalyx damage: “Glycocalyx damage, evidenced by increased levels of circulating syndecan-1 [43], can range from discrete disturbances in the composition of the most luminal layer, to excessive destruction and degradation, with loss of the entire glycocalyx [50,51]. Clinically, glycocalyx and endothelial cell damage are associated with pathophysiologic sequels like capillary leakage and tissue edema, accelerated inflammation and platelet activation, microvascular thrombus formation, loss of vascular responsiveness, hypotension, microcirculatory collapse and (multiple) organ failure.” (Ostrowski et al., page 6, col. 2, para. 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the PolyHSA of Palmer to increase nitric oxide production to treat endothelial dysfunction as described by Su and arrive at the claimed invention. This would necessarily result in decreased biomarkers for endothelial dysfunction such as syndecan-1, which is indicative of glycocalyx damage as disclosed by Zhang and in turn associated with syndecan-1 as disclosed by Ostrowski.
A person of ordinary skill in the art would be motivated to use PolyHSA in this way because as Zhang discloses: “Endothelial cell dysfunction (ECD) is the bedrock of diverse cardiovascular, renal, and metabolic diseases.” (Zhang et al., page 421, col. 1, para. 1), treating ECD is a desirable outcome for subjects. Palmer discloses above that viscous plasma expanders can modulate nitric oxide production and this in turn creates the benefits described by Su above.
A person would have a reasonable expectation of success due to how these factors are connected. A person of ordinary skill in the art would expect the PolyHSA of Palmer to modulate the nitric oxide levels as disclosed by Palmer, which treats endothelial dysfunction as disclosed by Su. A person of ordinary skill in the art would expect biomarkers associated with endothelial dysfunction, such as sydecan-1, to decrease as the endothelial dysfunction phenotype is improved by treatment with PolyHSA plasma expander therapy.
Consequently, claim 8 is obvious over Palmer et al. in view of Su et al., Zhang et al., and Ostrowski et al. and rejected.
Regarding claim 11, claim 8 is obvious as described above. Claim 11 further recites the case wherein the biomarker for endothelial dysfunction comprises syndecan-1.
As described above, Zhang and Ostrowski disclose the relationship between syndecan-1 and endothelial dysfunction.
Consequently, claim 11 is obvious over Palmer et al. in view of Su et al., Zhang et al., and Ostrowski et al. and rejected.
Regarding claim 15, claim 8 is obvious as described above. Claim 15 further recites the case wherein the PolyHSA is administered via infusion or exchange transfusion.
Palmer discloses: “For this use, a PolyHSA composition is infused into the circulatory system of the subject in a volume sufficient to restore the capacity of the circulatory system to perfuse tissues during a hypovolemic crisis, such as through intravenous or intraarterial infusion through a catheter.” (Palmer et al., para. [0023]).
Consequently, claim 15 is obvious over Palmer et al. in view of Su et al., Zhang et al., and Ostrowski et al. and rejected.
Regarding claim 16, claim 8 is obvious as described above. Claim 15 further recites the case wherein the PolyHSA is administered via infusion.
Palmer discloses: “For this use, a PolyHSA composition is infused into the circulatory system of the subject in a volume sufficient to restore the capacity of the circulatory system to perfuse tissues during a hypovolemic crisis, such as through intravenous or intraarterial infusion through a catheter.” (Palmer et al., para. [0023]).
Consequently, claim 16 is obvious over Palmer et al. in view of Su et al., Zhang et al., and Ostrowski et al. and rejected.
Regarding claim 23, claim 8 is obvious as described above. Claim 23 further recites the case wherein the PolyHSA is administered in a therapeutically effective amount to improve vascular integrity.
Palmer discloses that monomeric HSA can improve vascular integrity: “Monomeric HSA also has desirable antioxidant properties, inhibits inflammation during resuscitation, and has been shown to increase vascular integrity, thereby limiting extravasation of itself and other plasma proteins.” (Palmer et al., para. [0006]).
A person of ordinary skill in the art would have a reasonable expectation that PolyHSA would have the same ability to improve vascular integrity as monomeric HSA formulations and would be motivated to improve vascular integrity to improve microvascular perfusion through the capillaries.
Consequently, claim 23 is obvious over Palmer et al. in view of Su et al., Zhang et al., and Ostrowski et al. and rejected.
Regarding claim 24, claim 8 is obvious as described above. Claim 23 further recites the case wherein the PolyHSA has a molecular weight ranging from 100 kDa to 50,000 kD.
Palmer discloses a PolyHSA with a weight of 1,997 +/- 102 kDa (Palmer et al., para. [0034]).
Consequently, claim 24 is obvious over Palmer et al. in view of Su et al., Zhang et al., and Ostrowski et al. and rejected.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Palmer et al. (US 20120046231, published 2/23/2012) in view of Rowan et al. (Rowan, et al. American Journal of Physiology-Lung Cellular and Molecular Physiology 315.4: L476-L484. (2018) and Walker et al. (Walker, et al. ASME International Mechanical Engineering Congress and Exposition. Vol. 44267. (2010).
Regarding claim 12, claim 12 recites a method of treating endothelial dysfunction in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of PolyHSA to reduce endothelial barrier permeability.
Palmer et al. discloses administration of PolyHSA as a plasma expander: “In use, PolyHSA is utilized as a plasma replacement composition such as a PE to restore the capacity of the circulatory system to perfuse tissues during a hypovolemic crisis without the substantial side effects that can result from other PE compositions. For this use, a PolyHSA composition is infused into the circulatory system of the subject in a volume sufficient to restore the capacity of the circulatory system to perfuse tissues during a hypovolemic crisis, such as through intravenous or intraarterial infusion through a catheter.: (Palmer et al. para. [0023]).
Palmer does not specifically disclose the usage of PolyHSA to reduce endothelial barrier permeability.
However, Walker et al. discloses that reduced endothelial barrier permeability is a known benefit of synthetic colloids: “The main complications associated with the administration of large volumes of synthetic colloids include hypersensitivity reactions, potential anti-coagulation effects and impairment to post-surgical hemostasis. Far less attention has been paid to the potential benefits of these agents when administered in smaller doses. These benefits include improved organ perfusion and tissue oxygenation, a reduction of inflammation and endothelial activation, and decreased capillary permeability and tissue edema.” (Walker, et al., page 2, col. 1, para. 4).
Furthermore, Rowan et al. discloses that a high viscosity solution can reduce endothelial barrier permeability: “In further, independent experiments, we examined the effect of HVS on endothelial barrier function during extended steady-state perfusion. Each SS (LFR) perfused lung preparation was perfused until edema developed (median period 114 min, IQR 70–128), and a matched lung was then perfused with HVS (LFR) at the same low flow rate for an identical interval.
Mean wet-to-dry weight ratio was significantly higher (P < 0.001) in the SS-perfused lungs than in the HVS-perfused lungs, confirming the presence of edema (Fig. 4A). Extravasation of Evans Blue-labeled albumin was reduced by approximately one-half (P < 0.001) in the HVS-perfused lungs compared with that in SS (LFR) lungs (Fig. 4B), demonstrating that perfusion with HVS (LFR) reduced endothelial barrier permeability.” (Rowan et al., page L480, col. 1, para. 4).
Palmer discloses that PolyHSA solutions are high viscosity: “The viscosities of all PolyHSA solutions are higher than the viscosity of HSA at the same total protein concentration. This effect is likely due to the large increase in the weight averaged MW of the PolyHSA solutions, which increases the frequency of molecular interactions between neighboring PolyHSA molecules in solution and increases the solution viscosity.” (Palmer et al., para. [0039]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the PolyHSA of Palmer to produce the benefit of reduced endothelial barrier permeability as described by Rowan and Walker.
A person of ordinary skill in the art would be motivated to use PolyHSA in this manner because the endothelial barrier is important for fluid balance in pulmonary microcirculation: “Fluid filtration in the pulmonary microcirculation depends on the hydrostatic and oncotic pressure gradients across the endothelium and the selective permeability of the endothelial barrier. Maintaining normal fluid balance depends both on specific properties of the endothelium and of the perfusing blood.” (Rowan et al., page L476, Abstract).
A person of ordinary skill in the art would have a reasonable expectation of success because Palmer discloses that PolyHSA is a high viscosity solution and Rowan describes how high viscosity solutions result in reduced endothelial barrier permeability. Walker describes how this is a known benefit of synthetic colloids in general.
Consequently, claim 12 is obvious over Palmer et al. in view of Rowan et al. and Walker et al.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Palmer et al. (US 20120046231, published 2/23/2012) in view of Su (Su, Jin Bo. World journal of cardiology 7.11: 719 (2015)), Zhang et al. (Zhang, et al. Matrix Biology 71: 421-431 (2018)), and Ostrowski et al. (Ostrowski, et al. Critical care 19.1: 191 (2015)) as applied claim 8 above, further in view of Tang et al. (Tang, et al. Pflügers Archiv-European Journal of Physiology 459.6: 995-1004 (2010)).
Regarding claim 14, claim 8 is obvious as described above. Claim 14 further recites the case wherein the subject has a normal blood pressure.
Palmer, Su, Zhang, and Ostrowski does not specifically discuss a subject with normal blood pressure.
However, Tang discloses that treating blood pressure does not necessarily treat endothelial dysfunction: “Blood pressure reduction per se does not guarantee improvement in endothelial dysfunction. Other antihypertensive drugs, such as conventional β-adrenergic blockers, reduce arterial blood pressure but fail to restore normal endothelial function.” (Tang et al., page 1000, col. 2, para. 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the method of Palmer, Su, Zhang, and Ostrowski on a subject with normal blood pressure.
A person of ordinary skill in the art would be motivated to use PolyHSA in this way because as Zhang discloses: “Endothelial cell dysfunction (ECD) is the bedrock of diverse cardiovascular, renal, and metabolic diseases.” (Zhang et al., page 421, col. 1, para. 1), treating ECD is a desirable outcome for subjects. Palmer discloses above that viscous plasma expanders can modulate nitric oxide production and this in turn creates the benefits described by Su above. Furthermore, Tang discloses that endothelial dysfunction can persist through blood pressure regulation. Therefore, a person of ordinary skill in the art would use the PolyHSA to treat ECD even in the case of reduced or normal blood pressure.
A person would have a reasonable expectation of success due to how these factors are connected. A person of ordinary skill in the art would expect the PolyHSA of Palmer to modulate the nitric oxide levels as disclosed by Palmer, which treats endothelial dysfunction as disclosed by Su. A person of ordinary skill in the art would expect biomarkers associated with endothelial dysfunction, such as sydecan-1, to decrease as the endothelial dysfunction phenotype is improved by treatment with PolyHSA plasma expander therapy. Nothing about this changes in the case of a subject with normal blood pressure.
Consequently, claim 14 is obvious over Palmer et al. in view of Su et al., Zhang et al., and Ostrowski et al. as applied to claim 8 above, further in view of Tang et al. and rejected.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Palmer et al. (US 20120046231, published 2/23/2012) in view of Su (Su, Jin Bo. World journal of cardiology 7.11: 719 (2015)), Zhang et al. (Zhang, et al. Matrix Biology 71: 421-431 (2018)), and Ostrowski et al. (Ostrowski, et al. Critical care 19.1: 191 (2015)) as applied claim 8 above, further in view of Chatpun et al. (Chatpun, et al. The American journal of emergency medicine 31.1: 54-63 (2013)) and Tsai et al. (Tsai, et al. Biorheology 38.2-3: 229-237 (2001)).
Regarding claim 17, claim 16 is obvious as described above. Claim 17 further recites the case wherein the infusion comprises infusion of a volume of a composition comprising the PolyHSA, and wherein the volume comprises from 10% to 30% of the subject's total blood volume.
Palmer, Su, Zhang, and Ostrowski do not specifically disclose the case wherein the volume comprises from 10% to 30% of the subject's total blood volume.
However, Chatpun et al. discloses that 20% of total blood volume may be infused: “
Anesthetized hamsters were hemorrhaged by withdrawing 40% of the animal's BV (estimated as 7% of body weight) via the femoral artery catheter within 15 minutes. The hypovolemic shock condition was maintained for 30 minutes. Resuscitation was implemented by infusion of 50%
of the shed BV (20% of BV) of test solutions via jugular vein catheter within 10 minutes.” (Chatpun et al., page 57, col. 1, para. 3).
The range of blood infusion disclosed by Tsai reads the 10%-30% claimed. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
A person or ordinary skill in the art would have a reasonable expectation of success because animal models are frequently employed for protocol development and Tsai discloses that up to 50% blood volume can be exchanged: “Isovolemic substitution of RBCs with a colloidal or crystalloid solution, hemodilution, is safe as repeatedly validated on a systemic basis [40] for exchanges up to 50% of the RBCmass. A 50% substitution of RBCs brings the concentration of hemoglobin to the transfusion trigger, generally accepted to be in the neighborhood of 7 g Hb/dl. At this hematocrit in normal organisms tissue oxygen, blood pressure and functional capillary density (FCD) are normal. Microvascular conditions change when this threshold is passed.” (Tsai et al., page 231, para. 1).
Consequently, claim 17 is obvious over Palmer et al., Su et al., Zhang et al., and Ostrowski et al. as applied to claim 16 above, further in view of Chatpun et al. and Tsai et al. and rejected.
Claims 18 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Palmer et al. (US 20120046231, published 2/23/2012) in view of Su (Su, Jin Bo. World journal of cardiology 7.11: 719 (2015)), Zhang et al. (Zhang, et al. Matrix Biology 71: 421-431 (2018)), and Ostrowski et al. (Ostrowski, et al. Critical care 19.1: 191 (2015)) as applied claim 8 above, further in view of Tsai et al. (Tsai, et al. Biorheology 38.2-3: 229-237 (2001)).
Regarding claim 18, claim 8 is obvious as described above. Claim 18 further recites the case wherein the PolyHSA is administered via exchange transfusion.
Palmer discloses that PolyHSA is to be used in transfusion medicine: “The present invention relates generally to solutions to be used in transfusion medicine and more particularly to polymerized human serum albumin for use in transfusion medicine.” (Palmer et al., para. [0003].)
Furthermore, Tsai discloses that colloidal solutions such as PolyHSA in exchanges:
“Isovolemic substitution of RBCs with a colloidal or crystalloid solution, hemodilution, is safe as repeatedly validated on a systemic basis [40] for exchanges up to 50% of the RBCmass. A 50% substitution of RBCs brings the concentration of hemoglobin to the transfusion trigger, generally accepted to be in the neighborhood of 7 g Hb/dl. At this hematocrit in normal organisms tissue oxygen, blood pressure and functional capillary density (FCD) are normal. Microvascular conditions change when this threshold is passed.” (Tsai et al., page 231, para. 1).
Consequently, claim 18 is obvious over Palmer et al., Su et al., Zhang et al., and Ostrowski et al. as applied to claim 8 above, further in view of Tsai et al. and rejected.
Regarding claim 19, claim 18 is obvious as described above. Claim 19 further recites the case wherein the exchange transfusion comprises exchange transfusion of from 5% to 50% of the subject's total blood volume with a composition comprising the PolyHSA.
Palmer, Su, Zhang, and Ostrowski do not specifically disclose the case wherein the volume comprises exchange transfusion of from 5% to 50% of the subject's total blood volume with a composition comprising the PolyHSA.
However, Tsai discloses that the volume exchanged may be up to 50%:
“Isovolemic substitution of RBCs with a colloidal or crystalloid solution, hemodilution, is safe as repeatedly validated on a systemic basis [40] for exchanges up to 50% of the RBCmass. A 50% substitution of RBCs brings the concentration of hemoglobin to the transfusion trigger, generally accepted to be in the neighborhood of 7 g Hb/dl. At this hematocrit in normal organisms tissue oxygen, blood pressure and functional capillary density (FCD) are normal. Microvascular conditions change when this threshold is passed.” (Tsai et al., page 231, para. 1).
The range of blood exchange disclosed by Tsai, 0%-50%, overlaps the 5%-50% claimed here. MPEP 2144.05(I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Consequently, claim 19 is obvious over Palmer, Su, Zhang, and Ostrowski as applied to claim 18 above, further in view of Tsai and rejected.
Claims 20 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Palmer et al. (US 20120046231, published 2/23/2012) in view of Su (Su, Jin Bo. World journal of cardiology 7.11: 719 (2015)), Zhang et al. (Zhang, et al. Matrix Biology 71: 421-431 (2018)), and Ostrowski et al. (Ostrowski, et al. Critical care 19.1: 191 (2015)) as applied claim 8 above, further in view of Utariani et al. (Utariani, et al. Folia Medica Indonesiana 52.4: 310-315 (2017)).
Regarding claim 20, claim 8 is obvious as described above. Claim 20 further recites the case wherein the PolyHSA is administered in an amount effective to reduce circulating cytokine levels by at least 5%, such as from 5% to 70%.
Palmer, Su, Zhang, and Ostrowski do not specifically disclose the case wherein the PolyHSA is administered in an amount effective to reduce circulating cytokine levels by at least 5%, such as from 5% to 70%.
However, Utariani discloses that cytokine levels and serum albumin levels are known to be related in an inverse relationship: “The result is a significant correlation between albumin infusion with changes in serum albumin levels, IL6, TNF-α and SOFA score. Infusion of albumin positively correlated with increased levels of serum albumin and a negative correlation with the levels of IL6, TNF-α and SOFA scores where after infusion of albumin obtained a decrease of three.” (Utariani et al., page 312, col. 1, para. 3).
It would have been obvious to a person of ordinary skill in the art to use the method of Palmer, Su, Zhang, and Ostrowski to modulate cytokine levels based off the disclosure of Utariani to arrive at the claimed invention after routine optimization.
MPEP 2144.05(II) states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”
A person of ordinary skill in the art would be motivated to reduce cytokine levels because too many can cause organ damage: “Although cytokines play an important role in homeostasis, the production and release of excess will cause further tissue damage and organ dysfunction (Damas et al 1992). TNF-α, IL-1 and IL-6 is a cytokine that has a crucial role in the inflammatory process caused by infection.” (Utariani et al., page 310, col. 2, para. 1).
A person of ordinary skill in the art would have a reasonable expectation of success because Utariani shows that serum albumin can modulate cytokine levels and the claimed reduction can be achieved through routine experimentation for a dosage level.
Consequently, claim 20 is obvious over Palmer, Su, Zhang, and Ostrowski as applied to claim 8 above, further in view of Utariani et al. and rejected.
Regarding claim 21, claim 8 is obvious as described above. Claim 20 further recites the case wherein the PolyHSA is administered in an amount effective to reduce an immune response.
Palmer, Su, Zhang, and Ostrowski do not specifically disclose the case wherein the PolyHSA is administered in an amount effective to reduce an immune response.
However, Utariani discloses that cytokine levels and serum albumin levels are known to be related in an inverse relationship: “The result is a significant correlation between albumin infusion with changes in serum albumin levels, IL6, TNF-α and SOFA score. Infusion of albumin positively correlated with increased levels of serum albumin and a negative correlation with the levels of IL6, TNF-α and SOFA scores where after infusion of albumin obtained a decrease of three.” (Utariani et al., page 312, col. 1, para. 3).
Furthermore, cytokines are an immune response: “Cytokines are proteins formed by cells in the body as a form of defense against infection process, wound healing and other essential functions.” (Utariani et al., page 310, col. 2, para. 1).
It would have been obvious to a person of ordinary skill in the art to use the method of Palmer, Su, Zhang, and Ostrowski to modulate cytokine levels (an immune response) based off the disclosure of Utariani to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to reduce cytokine levels because too many can cause organ damage: “Although cytokines play an important role in homeostasis, the production and release of excess will cause further tissue damage and organ dysfunction (Damas et al 1992). TNF-α, IL-1 and IL-6 is a cytokine that has a crucial role in the inflammatory process caused by infection.” (Utariani et al., page 310, col. 2, para. 1).
A person of ordinary skill in the art would have a reasonable expectation of success because Utariani shows that serum albumin can modulate cytokine levels.
Consequently, claim 21 is obvious over Palmer, Su, Zhang, and Ostrowski as applied to claim 8 above, further in view of Utariani et al. and rejected.
Claims 22 is rejected under 35 U.S.C. 103 as being unpatentable over Palmer et al. (US 20120046231, published 2/23/2012) in view of Su (Su, Jin Bo. World journal of cardiology 7.11: 719 (2015)), Zhang et al. (Zhang, et al. Matrix Biology 71: 421-431 (2018)), and Ostrowski et al. (Ostrowski, et al. Critical care 19.1: 191 (2015)) as applied claim 8 above, further in view of Zhang et al. 2(Zhang, et al. Cardiovascular research 55.4: 820-829 (2002)).
Regarding claim 22, claim 8 is obvious as described above. Claim 22 further recites the case wherein the PolyHSA is administered in a therapeutically effective amount to reduce the number of leukocytes adhered to endothelial tissue in the subject.
Palmer, Su, Zhang, and Ostrowski do not specifically disclose the case wherein the PolyHSA is administered in a therapeutically effective amount to reduce the number of leukocytes adhered to endothelial tissue in the subject.
However, Zhang 2 discloses that serum albumin reduces monocyte adhesion to endothelial cells: “In the present study, we show for the first time that physiological concentrations of albumin selectively inhibit TNFα-induced VCAM-1 expression, monocyte adhesion and NF-κB activation in human aortic endothelial cells. These effects appear to be specific, since γ-globulin, a major serum protein unrelated to albumin, does not affect adhesion molecule expression.” (Zhang et al. 2, page 827, col. 1, para. 2).
A person of ordinary skill in the art would be motivated to block leukocyte-endothelial interactions in order to reduce inflammatory damage: “Leukocyte recruitment to the arterial wall plays a critical role in inflammation and atherosclerosis [1,2] and requires the coordinated expression of cellular adhesion molecules on the endothelium, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin [2,3]. The expression of these adhesion molecules is induced by various stimuli, including tumor necrosis factor-α (TNFα), interleukin-1β, bacterial endotoxin and certain reactive oxygen species [2,3]. Therapeutic agents that block endothelial activation and leukocyte–endothelial interactions can also markedly inhibit inflammatory responses in vivo.” (Zhang et al. 2, page 820, col. 1, para. 1).
A person of ordinary skill in the art would have a reasonable expectation of success because Zhang 2 discloses that serum albumin reduces monocyte adhesion to endothelial cells: “In the present study, we show for the first time that physiological concentrations of albumin selectively inhibit TNFα-induced VCAM-1 expression, monocyte adhesion and NF-κB activation in human aortic endothelial cells. These effects appear to be specific, since γ-globulin, a major serum protein unrelated to albumin, does not affect adhesion molecule expression.” (Zhang et al. 2, page 827, col. 1, para. 2).
Consequently, claim 22 is obvious over Palmer, Su, Zhang, and Ostrowski as applied to claim 8 above, further in view of Zhang et al. 2 and rejected.
Response to Arguments
Palmer in view of Su, Zhang, Ostrowski, Tang, Chatpun, Tsai, Utariani, Zhang 2, alone or in combination
Applicant's arguments filed 6/10/2026 have been fully considered but they are not persuasive.
Applicant Reply, page 7, para. 2 states: ” However, Palmer is silent with regards to specifically using polyHSA to treat endothelial dysfunction.”
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant Reply, page 7, para. 5 states: “Nothing in Palmer, Su, Zhang, Ostrowski, Tang, Chatpun, Tsai, Utariani, or Zhang 2 would have suggested to one of ordinary skill in the art that administration of polyHSA would treat endothelial dysfunction in a subject restoring impaired microvascular function, decreasing cytokines levels, and thus improving the mean survival time by double compared to animals that did not received polyHSA.”
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., restoring impaired microvascular function) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant fails to show why the logic applied in the above U.S.C. 103 arguments for claims 8, 11, 15-16, 23, and 24 is invalid. Palmer teaches the usage of polyHSA to increase blood viscosity, leading to increased NO production. Su teaches said NO production results in positive outcomes such as vasodilation and anti-inflammation. Said positive outcomes will reasonably reduce glycocalyx production as disclosed by Zhang which in turn reduces the circulating syndecan-1 as disclosed by Ostrowski.
MPEP 2144(IV) states: “The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."); In re Lintner, 458 F.2d 1013, 173 USPQ 560 (CCPA 1972) (discussed below); In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990), cert. denied, 500 U.S. 904 (1991) (discussed below).”
Applicant has failed to show why a person of ordinary skill in the art would not use this fact pattern in the prior art as motivation to use polyHSA to reduce circulating biomarkers for endothelial dysfunction nor why there would not be a reasonable expectation of success.
For these reasons, the amended claims are obvious over Palmer, Su, Zhang, Ostrowski, Rowan, Walker, Tang, Chatpun, Tsai, Utariani, and Zhang 2, alone or in combination.
Palmer in view of Rowan and Walker
Applicant Reply, page 9, para. 1 states: “Nothing in Palmer, Walker, and Rowan would have suggested to one of ordinary skill in the art that administration of polyHSA would treat endothelial dysfunction in a subject restoring impaired microvascular function including restoration of systemic hemodynamics, microcirculatory hemodynamics, and vascular permeability, thus improving the mean survival time by double compared to animals that did not received polyHSA.”
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., subject restoring impaired microvascular function including restoration of systemic hemodynamics, microcirculatory hemodynamics, and vascular permeability, thus improving the mean survival time by double compared to animals that did not received polyHSA.) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant has failed to show why a person of ordinary skill in the art would not be motivated use a high viscosity solution such as PolyHSA as disclosed by Palmer to achieve the benefits as disclosed by Walker and Rowan nor why a person of ordinary skill in the art would not have a reasonable expectation of success.
For these reasons, the amended claims are obvious over Palmer, Rowan, and Walker.
New 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.
Claim 27 is rejected under 35 U.S.C. 103 as being unpatentable over Palmer et al. (US 20120046231, published 2/23/2012) in view of Rowan et al. (Rowan, et al. American Journal of Physiology-Lung Cellular and Molecular Physiology 315.4: L476-L484. (2018) and Walker et al. (Walker, et al. ASME International Mechanical Engineering Congress and Exposition. Vol. 44267. (2010) as applied to claim 12 above, further in view of Endemann et al. (Endemann, "Endothelial dysfunction." Journal of the American Society of Nephrology 15.8: 1983-1992. (2004)).
Regarding claim 27, claim 12 is obvious as described above. Claim 12 further recites the case wherein the subject has normal blood pressure.
Palmer discloses that polyHSA is a plasma expander but also a solution with high viscosity: “The viscosities of all PolyHSA solutions are higher than the viscosity of HSA at the same total protein concentration. This effect is likely due to the large increase in the weight averaged MW of the PolyHSA solutions, which increases the frequency of molecular interactions between neighboring PolyHSA molecules in solution and increases the solution viscosity.” (Palmer et al., para. [0039]).
Palmer discloses that blood viscosity can activate the synthesis of NO: “Blood viscosity is an important factor that regulates the responses of the cardiovascular system, as it affects shear stress and activates the synthesis of vascular relaxation mediators such as nitric oxide (NO). NO is a critical regulator of basal blood vessel tone and vascular homeostasis, anti-platelet activity, modulation of endothelial and smooth muscle proliferation, and adhesion molecule expression.” (Palmer et al., para. [0007].)
Palmer also discloses the relationship between blood viscosity and NO production: “It has been erroneously perceived that lowering blood viscosity leads to an overall health benefit by decreasing peripheral vascular resistance and heart workload. On the contrary, plasma replacement compositions with a high viscosity increase the blood vessel wall shear stress, which induces endothelial cells to produce NO that dilates the blood vessels. Therefore, vascular resistance and heart workload may be decreased in patients with low Hct or blood volume via a high viscosity plasma replacement composition. The viscosity of a plasma replacement composition can be increased by increasing its MW or concentration or a combination of both.” (Palmer et al., para. [0041]).
Endemann discloses that said NO production is beneficial for treating endothelial dysfunction: “One of the most important vasodilating substances released by the endothelium is NO, which acts as a vasodilator, inhibits growth and inflammation, and has anti-aggregant effects on platelets. Reduced NO has often been reported in the presence of impaired endothelial function. It may result from reduced activity of endothelial NO synthase (eNOS; as a result of endogenous or exogenous inhibitors or reduction in the availability of its substrate, L-arginine) and to decreased bioavailability of NO.” (Endemann et al., page 1984, col. 1, para. 4).
Endemann also discloses that endothelial dysfunction can be symptom-free:
“Endothelial dysfunction was first described in human hypertension in the forearm vasculature in 1990 (4). Impaired vasodilation in hypertension has been confirmed by many studies in different vascular beds, including small resistance vessels (5,6). In stage I essential hypertension, we have shown that ∼60% of patients exhibit impaired small artery vasodilation when this is studied in vitro on vessels dissected from gluteal subcutaneous biopsies (7). Impairment of vasodilation has also been described in type 1 (8) and type 2 diabetes (9–11), coronary artery disease (12), congestive heart failure (13), and chronic renal failure (14–16). Moreover, this manifestation of endothelial dysfunction not only is associated with cardiovascular disease but may also precede its development, as shown in a study of offspring of hypertensive patients (17). The study subjects displayed endothelial dysfunction despite being normotensive. Another study showed endothelial dysfunction in symptom-free children and young adults at high risk for atherosclerosis (18). Also, in normotensive, normoglycemic, first-degree relatives of patients with type 2 diabetes, endothelial dysfunction was correlated with insulin resistance (19). Endothelial dysfunction has been demonstrated in the metabolic syndrome and in dyslipidemia (20) and may be associated with obesity (21), hyperhomocysteinemia (22), sedentary lifestyle (23), and smoking (24), in the absence of overt cardiovascular disease. (Endemann et al., page 1983, col. 2, para. 3, emphasis added).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the method of Palmer, Walker, and Rowan to treat a subject with endothelial dysfunction with normal blood pressure as disclosed by Endemann to arrive at the claimed invention because treatment of the negative effects of endothelial dysfunction is still valuable even in the absence of symptoms.
A person of ordinary skill in the art would be motivated to provide this treatment because of the negative effects disclosed by Endemann and would have a reasonable expectation of success because Endemann discloses that increased NO production is beneficial for treating endothelial dysfunction.
Consequently, claim 27 is rejected.
Claims 28 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Palmer et al. (US 20120046231, published 2/23/2012) in view of Rowan et al. (Rowan, et al. American Journal of Physiology-Lung Cellular and Molecular Physiology 315.4: L476-L484. (2018) and Walker et al. (Walker, et al. ASME International Mechanical Engineering Congress and Exposition. Vol. 44267. (2010).
Regarding claim 28, claim 12 is rejected as described above. Palmer discloses administration via infusion: “For this use, a PolyHSA composition is infused into the circulatory system of the subject in a volume sufficient to restore the capacity of the circulatory system to perfuse tissues during a hypovolemic crisis, such as through intravenous or intraarterial infusion through a catheter.” (Palmer et al. para. [0023]).
Consequently, claim 28 is rejected.
Regarding claim 29, claim 12 is rejected as described above. Palmer discloses: “The PolyHSA has a MW of least about 100 kDa and an upper limit of about 50,000 kDa.”
Consequently, claim 29 is rejected.
New Rejections-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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 8 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-63 of copending Application No. 19/582,384 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 8, the ‘384 application discloses claim 41:
“A method of treating endothelial dysfunction in a subject, the method comprising: administering to the subject a therapeutically effective amount of the composition of any of claims 1-31 to reduce circulating levels of a biomarker for endothelial dysfunction in the subject.”
The ‘384 application also discloses claims 1 and 2:
“A composition comprising polymerized albumin, wherein the composition comprises less than 5% by weight low molecular weight albumin species having a molecular weight less than 100 kDa; and less than 5% by weight high molecular weight albumin species.”
“The composition of claim 1, wherein the polymerized albumin comprises polymerized human serum albumin (PolyHSA).”
Consequently, claim 8 is anticipated by the ‘384 application and provisionally rejected.
Regarding claim 11, claim 8 is anticipated as described above.
The ‘384 application discloses claim 44:
“The method of any of claims 42-43, wherein the biomarker for endothelial dysfunction comprises syndecan-1.”
Consequently, claim 11 is anticipated by the ‘384 application and provisionally rejected.
Regarding claim 12, the ‘384 application discloses claim 45:
“A method of treating endothelial dysfunction in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of the composition of any of claims 1-31 to reduce endothelial barrier permeability.”
The ‘384 application also discloses claims 1 and 2:
“A composition comprising polymerized albumin, wherein the composition comprises less than 5% by weight low molecular weight albumin species having a molecular weight less than 100 kDa; and less than 5% by weight high molecular weight albumin species.”
“The composition of claim 1, wherein the polymerized albumin comprises polymerized human serum albumin (PolyHSA).”
Consequently, claim 12 is anticipated by the ‘384 application and provisionally rejected.
Regarding claim 14, claim 8 is anticipated as described above. Claim 47 of the ‘384 application discloses:
“The method of any one of claims 33-46, wherein the subject has a normal blood pressure.”
Consequently, claim 14 is anticipated by the ‘384 application and provisionally rejected.
Regarding claim 15, claim 8 is anticipated as described above. Claim 48 of the ‘384 application discloses:
“The method of any one of claims 33-47, wherein the composition of any of claims 1-31 is administered via infusion or exchange transfusion.”
Consequently, claim 15 is anticipated by the ‘384 application and provisionally rejected.
Regarding claim 16, claim 8 is anticipated as described above. Claim 49 of the ‘384 application discloses:
“The method of any one of claims 33-47, wherein the composition of any of claims 1-31 is administered via infusion.”
Consequently, claim 16 is anticipated by the ‘384 application and provisionally rejected.
Regarding claim 17, claim 16 is anticipated as described above. Claim 50 of the ‘384 application discloses:
“The method of claim 49, wherein the infusion comprises infusion of a volume of the composition of any of claims 1-31, and wherein the volume comprises from 10% to 30% of the subject's total blood volume.”
Consequently, claim 17 is anticipated by the ‘384 application and provisionally rejected.
Regarding claim 18, claim 8 is anticipated as described above. Claim 51 of the ‘384 application discloses:
“The method of any one of claims 33-47, wherein the composition of any of claims 1-31 is administered via exchange transfusion.”
Consequently, claim 18 is anticipated by the ‘384 application and provisionally rejected.
Regarding claim 19, claim 18 is anticipated as described above. Claim 52 of the ‘384 application discloses:
“The method of claim 51, wherein the exchange transfusion comprises exchange transfusion of from 5% to 90% of the subject's total blood volume with the composition of any of claims 1-31.”
This range substantially overlaps with the range of Applicant claim 19.
Consequently, claim 19 is obvious over the ‘384 application and provisionally rejected.
Regarding claim 20, claim 8 is anticipated as described above. Claim 53 of the ‘384 application discloses:
“The method of any one of claims 33-52, wherein the composition of any of claims 1-31 is administered in an amount effective to reduce circulating cytokine levels by at least 5%, such as from 5% to 70%.”
Consequently, claim 20 is anticipated by the ‘384 application and provisionally rejected.
Regarding claim 21, claim 8 is anticipated as described above. Claim 54 of the ‘384 patent discloses:
“The method of any one of claims 33-53, wherein the composition of any of claims 1-31 is administered in a therapeutically effective amount to reduce an immune response.”
Consequently, claim 21 is anticipated by the ‘384 application and provisionally rejected.
Regarding claim 22, claim 8 is anticipated as described above. Claim 55 of the ‘384 patent discloses:
“The method of any one of claims 33-54, wherein the composition of any of claims 1-31 is administered in a therapeutically effective amount to reduce the number of leukocytes adhered to endothelial tissue in the subject.”
Consequently, claim 22 is anticipated by the ‘384 application and provisionally rejected.
Regarding claim 23, claim 8 is anticipated as described above. Claim 56 of the ‘384 application discloses:
“The method of any one of claims 33-55, wherein the composition of any of claims 1-31 is administered in a therapeutically effective amount to improve vascular integrity.”
Consequently, claim 23 is anticipated by the ‘384 application and provisionally rejected.
Regarding claim 24, claim 8 is anticipated as described above. Claim 1 of the ‘384 application discloses a PolyHSA with a mass of 100kDa:
“A composition comprising polymerized albumin, wherein the composition comprises less than 5% by weight low molecular weight albumin species having a molecular weight less than 100 kDa; and less than 5% by weight high molecular weight albumin species.”
Consequently, claim 24 is anticipated by the ‘384 application and provisionally rejected.
Regarding claim 27, claim 12 is anticipated as described above. Claim 47 of the ‘384 application discloses:
“The method of any one of claims 33-46, wherein the subject has a normal blood pressure.”
Consequently, claim 27 is anticipated by the ‘384 application and provisionally rejected.
Regarding claim 28, claim 12 is anticipated as described above. Claim 48 of the ‘384 application discloses:
“The method of any one of claims 33-47, wherein the composition of any of claims 1-31 is administered via infusion or exchange transfusion.”
Consequently, claim 28 is anticipated by the ‘384 application and provisionally rejected.
Regarding claim 29, claim 12 is anticipated as described above. Claim 1 of the ‘384 application discloses a PolyHSA with a mass of 100kDa:
“A composition comprising polymerized albumin, wherein the composition comprises less than 5% by weight low molecular weight albumin species having a molecular weight less than 100 kDa; and less than 5% by weight high molecular weight albumin species.”
Consequently, claim 29 is anticipated by the ‘384 application and provisionally rejected.
Allowable Subject Matter
Claims 25 and 26 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Regarding claims 25 and 26, these claims further recite the case wherein the subject has sepsis or septic shock.
Applicant notes that Su et al. discloses:
” Results regarding the role of NO, particularly iNOS in septic shock are also elusive. Experiments in rats and in human blood cells showed that iNOS expression is correlated with cell apoptosis in septic shock[167,168]. Selective iNOS inhibition improved hemodynamics and mortality in nondiabetic rats with LPS-induced sepsis but not in diabetic rats[169], whereas depletion of iNOS resulted in increased dysfunctional mitochondria, IL-1β production and caspase-1 activation in response to LPS in myeloid cells from both mice and humans and increased NLRP3 inflammasome-mediated cytokine production and mortality in mice with LPS-induced sepsis, which was prevented by NLRP3 deficiency[170]. Although treatment with methylene blue that has the ability to scavenge NO and to inhibit NO synthase showed a transient and reproducible beneficial effect on systemic vascular resistance, arterial pressure and organ function in patients with septic shock, but its effect on mortality remains unknown[171,172].” (Su et al., page 725, col. 2, para. 2).
Upon further investigation, more recent prior art appears to confirm this phenomenon more clearly in Spiller et al. (Spiller, et al. Nitric Oxide 89: 32-40 (2019)):
“NO can react with superoxide anion (O2−) in aqueous solutions to yield peroxynitrite (ONOO−). Peroxynitrite oxidization of multiple targets leads to significant changes in lipids, proteins, and nucleic acids functioning. In sepsis, peroxynitrite contributes to damage in several tissues, including cardiovascular system, kidney, liver, central nervous system and immune system [45,46]. We observed that pretreatment of septic mice with the ONOO− scavengers uric acid (UA) or Tetrakis (FeTPPs) enhanced neutrophil rolling, adhesion, and migration to the focus of infection, improving infection control and survival rates [47].” (Spiller et al., page 34, col. 1, para. 2).
Consequently, the prior art teaches away from using methods that increase NO production in the case of sepsis. The methods recited by claims 25 and 26 are therefore novel and nonobvious. However, they are not allowable because of being dependent upon a rejected base claim.
Conclusion
No claim is allowed.
Claims 25 and 26 are objected to.
Claims 8, 11, 12, and 14-24 and 27-29 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to David Paul Bowles whose telephone number is (571)272-0919. The examiner can normally be reached Monday-Friday 8:30-5:00.
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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/JEANETTE M LIEB/Primary Examiner, Art Unit 1654
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