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 .
Election/Restrictions
Applicant’s election without traverse of Group II, claims 8 and 11-12, in the reply filed on 12/22/2025 is acknowledged.
Priority
Priority to US 63/074,751, filed 9/4/2020, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) were submitted on 3/6/2023, 10/15/2023, 8/23/2024, and 12/22/2025 before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 8, 11, 12, and 14-24 are pending. Claims 8, 11, 12, and 14-24 are under examination.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Regarding claim 20, 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).
Claim 20 is rejected.
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 and 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.
Conclusion
No claim is allowed.
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
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654