DETAILED ACTION
Examiner acknowledges receipt of the reply filed 11/06/2025, in response to the non-final office action mailed 5/06/2025.
Claims 1, 2, 4, 10-13, 15, 18, 22-24, 28-41, 43-46, 48, 50-55, and 64 are pending. Claim 5 has been canceled. Claims 30, 31, 39, 55 and 64 remain withdrawn for the reasons made of record..
Claims 1, 2, 4, 10-13, 15, 18, 22-24, 28, 29, 32-38, 40, 41, 43-46, 48, and 50-54 are being examined on the merits in this office 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 .
Drawings- withdrawn
The objection to the drawings is withdrawn in view of the filed 11/06/2025.
Claim Objections- withdrawn
The objection of claims 13, 15, 23, 43, and 48 is withdrawn in view of the amendment filed 11/06/2025.
Claim Rejections - 35 USC § 112- withdrawn
The rejection of claims 5, 10-12, 13, 15, 22, 23, 32, 33-38, 40, 41, 43-46, and 52-54 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of the amendment filed 11/06/25.
The rejection of claims 10-12, 32-38, 40, 41, and 52-54 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in view of the amendment filed 11/06/25.
Claim Rejections - 35 USC § 103- withdrawn
The rejection of claims 1, 2, 4, 5, 10-13, 15, 18, 24, 29, and 51 under 35 U.S.C. 103 as being unpatentable over Zhao et al (J Neurosci 29: 15819 –15827 (2009)), and further in view of Ishi (U.S. 4103687- cited in IDS filed 11/16/2021), is withdrawn in view of the amendment filed 11/06/2025.
The rejection of claims 1, 2, 4, 5, 10-13, 15, 18, 24, 29, 48, 50, and 51 under 35 U.S.C. 103 as being unpatentable over Zhao et al (J Neurosci 29: 15819 –15827 (2009)) and Ishi (U.S. 4103687- cited in IDS filed 11/16/2021), as applied to claims 1, 2, 4, 5, 10-13, 15, 18, 24, 29, and 51 above, and further in view of Dalton et al (U.S. 2008/293623- cited in IDS filed 11/16/2021), is withdrawn in view of the amendment filed 11/06/2025.
The rejection of claims 1, 2, 4, 5, 10-13, 15, 18, 24, 29, 48, 50, and 51-54 under 35 U.S.C. 103 as being unpatentable over Zhao et al (J Neurosci 29: 15819 –15827 (2009)), Ishi (U.S. 4103687- cited in IDS filed 11/16/2021), and Dalton et al (U.S. 2008/293623- cited in IDS filed 11/16/2021), as applied to claims 1, 2, 4, 5, 10-13, 15, 18, 24, 29, 48, 50, and 51 above, and further in view of Ehlert et al (J Neurosurg 124:51–58 (2016)), as evidenced by Bohme et al (European Heart Journal 4 (Suppl. C): 19-24 (1983)), is withdrawn in view of the amendment filed 11/06/2025.
Response to Arguments
Applicant’s arguments and amendment filed 11/06/2025 with respect to above objections and rejections have been fully considered and are persuasive. Objections and rejections have been withdrawn.
Applicant's arguments filed 11/06/2025 have been fully considered but they are not persuasive with respect to the maintained §112 rejections.
Upon further consideration, a new grounds of objection and rejection is made the claims filed 11/06/2025.
An action on the merits is set forth herein.
Specification
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
New Objections/ Rejections
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 should be amended to recite “and” between the last two recited wherein clauses.
Appropriate correction is required.
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.
Claims 22 and 23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. This is a new rejection necessitated by the amendment filed 11/06/2025.
Claim 22 recites the limitation "the amount". There is insufficient antecedent basis for this limitation in the claim.
Because claim 23 depends from indefinite claim 22 and do not clarify the point of confusion, they must also be rejected under 35 U.S.C. 112, second paragraph.
Maintained Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 4, 10-12, 29, 32-38, 40, 41, 43-46, 48, and 50-54 remain/are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This rejection is maintained from the office action mailed 5/06/2025, but has been amended to reflect claims filed 11/06/2025.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
The instant claims are drawn to a method of treating or preventing an adverse secondary neurological outcome in a subject who has experienced a hemorrhagic stroke accompanied by extravascular erythrolysis and release of cell-free hemoglobin (Hb) into the subject's cerebral spinal fluid (CSF), the method comprising exposing the subject's CSF to a therapeutically effective amount of exogenous haptoglobin (Hp) for a period of time sufficient to allow the Hp to form a complex with, and thereby neutralize, the cell-free Hb; wherein the period of time to which the subject's CSF is exposed to the therapeutically effective amount of Hp is up to 45 minutes; wherein the adverse secondary neurological outcome is selected from a delayed ischemic neurological deficit (DIND), delayed cerebral ischemia (DCI), neurotoxicity, inflammation, nitric oxide depletion, oxidative tissue injury, and cerebral edema and occurs within the subject's brain parenchyma.
The specification states at page 30:
The term “exposing”, as used herein, means bringing into contact the CSF with the Hp in such a way as to allow the Hp to bind to and form a complex with cell-free Hb (the predominant form of which will be oxyHb) that is present in the CSF, whereby the formation of Hb:Hp complexes substantially neutralizes the otherwise adverse biological effect of cell-free Hb on brain tissue.
The specification states at pp. 11-12:
The terms “treating”, “treatment” and the like are also used interchangeably herein to mean preventing an adverse secondary neurological outcome from occurring or delaying the onset or subsequent progression of an adverse secondary neurological outcome in a subject that may be predisposed to, or at risk of, developing an adverse secondary neurological outcome, but has not yet been diagnosed as having it. In that context, the terms “treating”, “treatment” and the like are used interchangeably with terms such as “prophylaxis”, “prophylactic” and “preventative”. It is to be understood, however, that the methods disclosed herein need not completely prevent an adverse secondary neurological outcome from occurring in the subject to be treated.
Under the broadest reasonable interpretation, the claimed methods encompass all routes of administration of haptoglobin for “exposing” the CSF to Hp. Examiner further notes that claims 43-46 read on “removing the CSF”. The claims and specification do not provide sufficient guidance as to whether a portion or all of the CSF is removed from the subject. It is questionable as to how a subject would survive if is the CSF is removed. Moreover, the animal model of sheep was very restricted to methodology (Fig 2) in a laboratory setting. There is limited written support for how the skilled artisan can extrapolate the methodology of “exposing the CSF to the therapeutically effective amount of Hp extracorporeally” (claim 29) to a subject in a clinical setting, e.g., human subject.
Examiner further notes there are no examples of preventing an adverse secondary neurological outcome.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is in possession of and what Applicant is claiming. The Federal Circuit has emphasized that "the hallmark of written description is disclosure" and "[t]hus, ‘possession as shown in the disclosure’ is a more complete formulation." Ariad, 598 F.3d at 1351, 94 USPQ2d at 1172. Accordingly, "the test requires an objective inquiry into the four corners of the specification from the perspective of a person of ordinary skill in the art" and "[b]ased on that inquiry, the specification must describe an invention understandable to that skilled artisan and show that the inventor actually invented the invention claimed." Id.
The specification reduced to practice an ex vivo model of slaughtered pigs and an in vivo model of sheep (as shown in Fig 2). Haptoglobin (Hp) was administered directly to the brain in the sheep model. Haptoglobin-hemoglobin (hp-hb complexes that were prepared and then added to the sheep model. In sheep dynamic 3D MRI, administration of hemoglobin and Hb:Hp complexes distributed into/localized to the subarachnoid space following injection into the lateral ventricle (p. 63). Haptoglobin was shown to bind/compartmentalize Hb in the CSF compartment (pp. 63-64). The specification indicates that figure 10 shows that Hb-Hp complexes remained compartmentalized in the CSF space. Page 65 indicates that hemoglobin in the subarachnoid space induces acute vasospasms in vivo. Coadministration of haptoglobin did not result in vasospasms (p. 65). Examiner expressly notes that this example is not correlative with the instant claim scope which encompasses a method of treating or preventing a recited adverse secondary neurological outcome following a hemorrhagic stroke. The specification teaches a prophetic example of a SAH patient (pages 67-68).
Vas-Cath Inc. v. Mahukar, 19USPQ2d 1111, clearly states, “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (see page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (see Vas-Cath at page 1116).
Adequate written description requires more than a mere statement that is part of the invention and reference to a potential method of using it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483.
Therefore, a method of treating or preventing a recited adverse secondary neurological outcome in a subject who has experienced a hemorrhagic stroke accompanied by extravascular erythrolysis and release of cell-free hemoglobin (Hb) into the subject’s cerebral spinal fluid (CSF), the method comprising exposing the subject’s CSF of a subject in need thereof to a therapeutically effective amount of exogenous haptoglobin (Hp) and for a period of time [up to 45 minutes] sufficient to allow the Hp to form a complex with, and thereby neutralize, the cell-free Hb has not met the written description provision of 35 U.S.C. 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision.
Applicant is directed to the Guidelines for the Examination of Patent Applications under the 35 U.S.C. 112(a), paragraph 1 “Written Description” Requirement. See MPEP § 2163 et seq.
Response to Arguments
Applicant traversed the rejection at pp. 10-11 of the reply filed 11/06/2025. Applicant states “Applicant respectfully disagrees with each of the objections and rejections” (reply at p. 10). Applicant did not provide any specific arguments with respect to the written description rejection.
The rejection is maintained for the reasons set forth herein, and those previously made of record.
Claims 1, 2, 4, 10-13, 15, 18, 22-24, 28, 29, 32-38, 40, 41, 43-46, 48, and 50-54 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating a recited adverse secondary neurological outcome following a hemorrhagic stroke accompanied by extravascular erythrolysis and release of cell-free hemoglobin (Hb) into the subject’s cerebral spinal fluid (CSF), does not reasonably provide enablement for preventing or prophylaxis an adverse secondary neurological outcome. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. This rejection is maintained from the office action mailed 5/06/2025, but has been amended to reflect claims filed 11/06/2025.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to:
(1) The breadth of the claims; (2) The nature of the invention; (3) The state of the prior art; (4) The level of one of ordinary skill; (5) The level of predictability in the art; (6) The amount of direction provided by the inventor; (7) The existence of working examples; and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Regarding factors (2) The nature of the invention and (1) The breadth of the claims: The claims are drawn to a method of treating or preventing an adverse secondary neurological outcome in a subject who has experienced a hemorrhagic stroke accompanied by extravascular erythrolysis and release of cell-free hemoglobin (Hb) into the subject's cerebral spinal fluid (CSF), the method comprising exposing the subject's CSF to a therapeutically effective amount of exogenous haptoglobin (Hp) for a period of time sufficient to allow the Hp to form a complex with, and thereby neutralize, the cell-free Hb; wherein the period of time to which the subject's CSF is exposed to the therapeutically effective amount of Hp is up to 45 minutes; wherein the adverse secondary neurological outcome is selected from a delayed ischemic neurological deficit (DIND), delayed cerebral ischemia (DCI), neurotoxicity, inflammation, nitric oxide depletion, oxidative tissue injury, and cerebral edema and occurs within the subject's brain parenchyma.
The specification states at pp. 11-12:
The terms “treating”, “treatment” and the like are also used interchangeably herein to mean preventing an adverse secondary neurological outcome from occurring or delaying the onset or subsequent progression of an adverse secondary neurological outcome in a subject that may be predisposed to, or at risk of, developing an adverse secondary neurological outcome, but has not yet been diagnosed as having it. In that context, the terms “treating”, “treatment” and the like are used interchangeably with terms such as “prophylaxis”, “prophylactic” and “preventative”. It is to be understood, however, that the methods disclosed herein need not completely prevent an adverse secondary neurological outcome from occurring in the subject to be treated.
(3) The state of the prior art:
Geraghty et al (Curr Atheroscler Rep 19: 50 pp. 1-12 (2017)-previously cited) is a review article teaches that Delayed cerebral ischemia (DCI) is common after subarachnoid hemorrhage (SAH) and represents a significant cause of poor functional outcome (abstract). Brain injury after SAH can be divided into early and delayed stages (Fig. 1). One of the earliest consequences of SAH is early brain injury (EBI), which typically occurs within the first 72 hours (pp. 1-2). Adverse secondary outcomes include nitric oxide depletion, cerebral edema, vasospasm, seizures, oxidative stress, and hydrocephalus (Fig. 1). Inflammation within the CNS after SAH begins with arterial rupture, as blood enters the subarachnoid space and releases signals that promote an inflammatory response (p. 7). Products normally found within erythrocytes such as hemoglobin are released into the subarachnoid space and can serve as damage-associated molecular patterns (DAMPs) recognized by innate immune cells. Heme can be metabolized by heme oxygenase in immune cells and generate bioactive and pro-inflammatory compounds. To prevent this damaging interaction, haptoglobin can bind hemoglobin and prevent its metabolism. Id.
De Oliveira Manoel et al, (Frontiers in neurology 9:1-12 (May 2018)- previously cited) teach that Aneurysmal subarachnoid hemorrhage (SAH) is a sub-type of hemorrhagic stroke associated with the highest rates of mortality and long-term neurological disabilities. Despite the improvement in the management of SAH patients and the reduction in case fatality in the last decades, disability and mortality remain high in this population. Brain injury can occur immediately and in the first days after SAH. This early brain injury can be due to physical effects on the brain such as increased intracranial pressure, herniations, intracerebral, intraventricular hemorrhage, and hydrocephalus. After the first 3 days, angiographic cerebral vasospasm (ACV) is a common neurological complication that in severe cases can lead to delayed cerebral ischemia and cerebral infarction (abstract). Neuroinflammation may play an important role in the damage of cerebral cells after SAH. The products of erythrocyte degradation in the subarachnoid space lead to the accumulation of hemoglobin and its products (i.e., methemoglobin, heme, and hemin), which activate toll-like receptor 4, initiating the inflammatory cascade. Microglia, the resident inflammatory cells in the central nervous system, are activated, which triggers the upregulation of a large number of endothelial adhesion molecules, allowing the inflammatory cells to reach the subarachnoid space (p. 6). Macrophages and neutrophils, once in the subarachnoid space, start the process of phagocytosis of the product of degraded red cells, with the attempt of removing the extravascular hemoglobin, the process of which may promote neuronal healing. The clearance of hemoglobin from subarachnoid space depends on and is accelerated by the ligation of hemoglobin to haptoglobin. The complex hemoglobin/haptoglobin is then phagocyted by immune cells. Id.
Zhao et al (J Neurosci 29: 15819 –15827 (2009)-previously cited) teach that after intracerebral hemorrhage (ICH), the brain parenchyma is exposed to blood containing red blood cells (RBCs) and consequently to its lysis products. Iron-rich hemoglobin (Hb) is the most abundant protein in RBCs. When released into the brain parenchyma during hemolysis, Hb becomes a central mediator of cytotoxicity (abstract). The red blood cell (RBC), a main cellular component of the hematoma, lyses within days and releases hemoglobin (Hb), which subsequently is degraded into heme and iron, cytotoxins representing a key contributor to secondary brain injury after ICH (p. 15819). Haptoglobin (Hp) is an acute-phase α2-acid response glycoprotein known to tightly bind Hb and form stable Hb–Hp complexes. By forming Hp–Hb complexes, Hp stabilizes and shields heme iron within the hydrophobic pocket of Hb, thereby preventing its pro-oxidative properties and cytotoxicity (p. 15819). Hp is produced principally in liver by hepatocytes and secreted into blood circulation. Locally produced brain Hp may protect the brain from Hb-mediated damage in the case of ICH. Id. Brain-derived Hp plays cytoprotective roles and represents a potential therapeutic target for ICH treatment (pp. 15821-15826).
(4) The relative skill of those in the art:
MPEP 2141.03 states (in part)” A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR International Co. v. Teleflex Inc., 127 S.Ct. 1727, 167 LEd2d 705, 82 USPQ2d 1385, 1397 (2007). “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. At 1396, 82 USPQ2d at 1396. The “hypothetical person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988) (disagreeing with the examiner’s definition of one of ordinary skill in the art (i.e. a doctorate level engineer or scientist working at least 40 hours per week in semiconductor research or development), and finding that the hypothetical person is not definable by way of credentials, and that the evidence in the application did not support the conclusion that such a person would require a doctorate or equivalent knowledge in science or engineering). In the instant case, the skill in the art high with respect to physicians and scientists. The level of skill in the art (physicians and scientists) would be high.
(5) The predictability or unpredictability of the art: The invention is directed toward the treatment of disease and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
It is noted that pharmaceutical and biological art is generally unpredictable, requiring each embodiment to be individually assessed for physiological activity. Given this fact, historically the development of new drugs has been difficult and time-consuming. Adding to the unpredictability is that many treatment options may show promise in animal models, but may fail to show therapeutic improvement in clinical trials. There is no absolute predictability, even in view of the high level of skill in the art.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The examples teach a sheep model oxyHb induced vasospasms. Animals were prepared as indicated in Fig 2 (pp. 56-58). Preparation of recombinant haptoglobin and isolated from plasma is taught at pp. 60-61. In animal models, wire biography experiments induced nitric oxide mediated vasodilation. Administration of Hp restored vasodilatory response (pp. 62-63). An ex vivo assay indicated that cell free hemoglobin is a major disruptor of arterial nitric oxide signaling in the CSF patients with aSAH (p. 63). In sheep dynamic 3D MRI, administration of hemoglobin and Hb:Hp complexes distributed into/localized to the subarachnoid space following injection into the lateral ventricle (p. 63). Haptoglobin was shown to bind/compartmentalize Hb in the CSF compartment (pp. 63-64). The specification indicates that figure 10 shows that Hb-Hp complexes remained compartmentalized in the CSF space. Page 65 indicates that hemoglobin in the subarachnoid space induces acute vasospasms in vivo. Coadministration of haptoglobin did not result in vasospasms (p. 65). Examiner expressly notes that this example is not correlative with the instant claim scope which encompasses a method of treating or preventing an adverse secondary neurological outcome following a hemorrhagic stroke. The specification teaches a prophetic example of a SAH patient (pages 67-68).
There are no examples of preventing an adverse secondary neurological outcome following a hemorrhagic stroke. In order to prevent an adverse secondary neurological outcome following a hemorrhagic stroke, the skilled artisan must be able to first predict and identify subjects that are at risk for developing an hemorrhagic stroke, as well as required effective amounts of haptoglobin in order to prevent the hemorrhagic stroke much less prevent any potential adverse secondary neurological outcomes.
(8) The quantity of experimentation necessary: Owing to factors 1-7 the quantity is expected to be high.
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is justified here.
Response to Arguments
Applicant traversed the rejection at pp. 10-11 of the reply filed 11/06/2025. Applicant states “Applicant respectfully disagrees with each of the objections and rejections” (reply at p. 10). Applicant did not provide any specific arguments with respect to the enablement rejection.
The rejection is maintained for the reasons set forth herein, and those previously made of record.
Closest Prior Art
Zhao et al (J Neurosci 29: 15819 –15827 (2009)-previously cited) teach that after intracerebral hemorrhage (ICH), the brain parenchyma is exposed to blood containing red blood cells (RBCs) and consequently to its lysis products. Iron-rich hemoglobin (Hb) is the most abundant protein in RBCs. When released into the brain parenchyma during hemolysis, Hb becomes a central mediator of cytotoxicity (abstract). The red blood cell (RBC), a main cellular component of the hematoma, lyses within days and releases hemoglobin (Hb), which subsequently is degraded into heme and iron, cytotoxins representing a key contributor to secondary brain injury after ICH (p. 15819) [reads on extravascular erythrolysis and release of cell-free hemoglobin into a cerebral spinal fluid]. Haptoglobin (Hp) is an acute-phase α2-acid response glycoprotein known to tightly bind Hb and form stable Hb–Hp complexes. By forming Hp–Hb complexes, Hp stabilizes and shields heme iron within the hydrophobic pocket of Hb, thereby preventing its pro-oxidative properties and cytotoxicity (p. 15819). Hp may protect the brain from Hb-mediated damage in the case of ICH. Id. Hp plays cytoprotective roles and represents a potential therapeutic target for ICH treatment (pp. 15821-15826).
However, the reference doesn’t expressly teach or suggest treating or preventing an adverse secondary neurological outcome, much less the timing of exposure of haptoglobin to the subject’s CSF.
Conclusion
No claims are allowed.
Claims 1, 2, 4, 10-13, 15, 18, 22-24, 28-41, 43-46, 48, 50-55, and 64 are pending. Claims 30, 31, 39, 55 and 64 are withdrawn.
Claims 1, 2, 4, 10-13, 15, 18, 22-24, 28, 29, 32-38, 40, 41, 43-46, 48, and 50-54 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTINA M HELLMAN whose telephone number is (571)272-2836. The examiner can normally be reached M-F 9:00 am-5:30 pm.
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/KRISTINA M HELLMAN/ Examiner, Art Unit 1654
/JULIE HA/ Primary Examiner, Art Unit 1654
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