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 .
Claim Status
Claims 1-2, 5, 11, 13, 19-20, 22, 26, 46-49, 51, 56-57, 59, 63, 85-87, 90-91, and 108 are pending. Claims 20, 26, 46-49, 51, 56-57, 59, 63, 85-87, 90-91, and 108 are withdrawn. Claims 1-2, 5, 11, 13, 19, and 22 are presently considered.
Election/Restriction
Applicant’s election without traverse of Group I and the species of Example 3 in the reply filed on 4/06/2026 is acknowledged.
The originally elected species of Example 3 is understood to be a “heme toxicity/hemopexin protection model in a murine striatal injection model, in which subjects were given heme-hemopexin (1 mM) with an infusion rate of 100 nl/s for 5 minutes” (see, e.g., Reply filed 4/06/2026 at § II).
Applicant alleges that the elected species reads upon all claims of Group I, but fails to identify or explain how the claims read upon the elected species (see, e.g., Reply filed 4/06/2026 at § II). Regarding claim 2, the “haemorrhagic stroke” is not “spontaneous”, but rather a “traumatic haemorrhage”, which would be reasonably understood in the animal model to be an intracerebral hemorrhage (ICH, bleeding within striatum tissue) (see Spec. filed 8/01/2023 at Example 3 at 83 at lines 5-20). Regarding claim 5, the adverse secondary neurological outcome is not specified, but is reasonably understood to include at least inflammation and cerebral oedema (see Spec. filed 8/01/2023 at Example 3 at 84, referring to perilesional edema and cerebral edema). Regarding claim 11 and within “about 21 days”, the exposure of CSF to Hx is understood to be within a few minutes of drilling a burrhole and instantly upon intracranial injection (see Spec. filed 8/01/2023 at Example 3 at 83 at lines 5-20). Regarding claim 13, administration is understood to be intracranial (see id). Regarding claim 19, infusion is for over 5 minutes, and therefore CFS exposure to Hx is “at least about 2 minutes” (see id). In addition, “CFS exposure to Hx” would presumably last until Hx was depleted from CFS. Regarding claim 22, in the elected species heme-hemopexin is administered at 1 mM (see id). Accordingly, the originally elected species is understood to read upon at least instant claims 1-2, 5, 11, 13, 19, and 22.
However, multiple claims within the scope of Group I do not reasonably appear to read upon the originally elected species, and Applicant failed to address or explain how the limitations of these claims were satisfied by the originally elected species. Claim 20 does not read upon the originally elected species, at least because no measuring step of CSF is present. Claim 26 does not read upon the originally elected species at least because no exposure of CSF extracorporeally or removal of complexes is present at Example 3. Claims 46-47 do not read upon the originally elected species, which is silent regarding how Hx is derived, and no admission that such limitations are obvious variants has been placed on record at this time. Claims 48-49, 51, 56-57, 59, 63, and 85-87 do not read upon the originally elected species at least because no additional step of administering haptoglobin in combination with heme-hemopexin is present in the originally elected species. Claims 90 and 91 do not read upon the originally elected species at least because no second agent (e.g., a vasodilator) was actually administered in the elected species as required by claim 90. Accordingly, the originally elected species does not read upon claims 20, 26, 46-49, 51, 56-57, 59, 63, 85-87, or 90-91, and no identification of whether or not such limitations define obvious variants or not has been placed on record at this time.
Following extensive search and examination, the originally elected species has been deemed anticipated and/or obvious in view of the prior art as applied below. Per MPEP § 803.02(III)(A),
Following election, the Markush claim will be examined fully with respect to the elected species and further to the extent necessary to determine patentability. Note that where a claim reads on multiple species, only one species needs to be taught or suggested by the prior art in order for the claim to be anticipated or rendered obvious...
If the Markush claim is not allowable, the provisional election will be given effect and examination will be limited to the Markush claim and claims to the elected species, with claims drawn to species patentably distinct from the elected species held withdrawn from further consideration.
Accordingly, claims 1-2, 5, 11, 13, 19, and 22 are rejected in view of the originally elected species and claims that do not read upon the originally elected species are withdrawn.
Claim 108 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/06/2026.
Claims 20, 26, 46-49, 51, 56-57, 59, 63, 85-87, or 90-91 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/06/2026.
Claims 1-2, 5, 11, 13, 19, and 22 are presently considered.
Priority
The priority claim to US Provisional Application 63/144043 as filed 2/01/2021 is acknowledged.
Information Disclosure Statement
The IDS filed 08/01/2023; 08/01/2023; 03/07/2024; and 04/22/2024 are each acknowledged and presently considered.
Applicant should note that one or more documents disclosed on the IDS form submitted on 3/07/2024 were not considered since they did not conform to 37 CFR 1.98(b) by providing a proper date, as 37 CFR 1.98(b) requires that each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue. See MPEP 609.04(a). Here, the earliest priority claim is to US Provisional Application 63/144043 as filed 2/01/2021; therefore, all documents published in 2020 or later must be accompanied by both month and date of publication.
References that were not considered have been indicated by strike-though on the attached IDS forms. Although not considered, these documents have been placed in the application file, but the information referred to therein has not been considered as to the merits. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Claim Interpretation
For purposes of examination, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
Claim 1 is representative of the pending claim scope and presently recites:
1. (Currently Amended) A method of treating or preventing an adverse secondary neurological outcome in a subject following a haemorrhagic stroke accompanied by extravascular erythrolysis and release of cell-free heme and/or cell-free haemoglobin (Hb) into a cerebral spinal fluid (CSF), the method comprising exposing the CSF of a the subject in need thereof to a therapeutically effective amount of hemopexin (Hx) and for a period of time sufficient to allow the Hx to form a complex with, and thereby neutralise, the cell-free heme.
Accordingly, the claims are directed to a method of treating or preventing adverse secondary neurological outcomes in subjects. Additional claim interpretations are set forth below.
The preamble stating “treating or preventing an adverse secondary neurological outcome in a subject following a haemorrhagic stroke accompanied by extravascular erythrolysis and release of cell-free heme and/or cell-free haemoglobin (Hb) into a cerebral spinal fluid (CSF)” is understood to limit the patient population to patients “in need thereof” a treatment for “treating or preventing” the recited condition. Additional interpretations are provided below.
“Haemorrhagic stroke”: A hemorrhagic stroke occurs when a blood vessel in the brain ruptures, causing bleeding that compresses brain tissue and restricts oxygen, leading to rapid brain cell death. A hemorrhagic stroke may be intracerebral (inside brain), subarachnoid (bleeding in the space between the blood and the skull), or intraventricular (inside fluid-filled spaces or ventricles) (wherein the types may overlap in scope depending on location of the bleed). A hemorrhagic stroke is defined as interchangeable with the terms “brain haemorrhage”, “cerebral haemorrhage”, and “intracranial haemorrhage” (see, e.g., Spec. filed 8/01/2023 at 10 at lines 1-15).
“Extravascular erythrolysis” (or hemolysis) is the premature destruction of red blood cells (RBCs) outside the bloodstream by macrophages. It is not defined or described in the specification, but is understood to occur when red blood cells enter cerebral spinal fluid, wherein upon hemolysis, the RBCs would release heme and hemoglobin.
Per MPEP § 2111.02, “where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation”. Here, the preamble is understood to recite an intended purpose, and is understood to define the “subject in need thereof” as a patient “following a haemorrhagic stroke” (but see MPEP § 2111.04(I), noting that “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure”).
“Comprising” is an open-ended transitional term (see, e.g., MPEP § 2111.03(I)), wherein additional steps or components are not excluded. However, “‘[c]omprising’ is a term of art used in claim language which means that the named elements are essential” (see, e.g., id.; see also Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997)).
The claim recites active method steps: “the method comprising exposing the CSF of a the subject in need thereof to a therapeutically effective amount hemopexin (Hx) and for a period of time sufficient to allow the Hx to form a complex with, and thereby neutralise, the cell-free heme”. The applicable interpretation is discussed below.
The phrase “exposing the CSF of a the [sic] subject” is understood to require “administering” Hx to a subject via any administration route that would result in Hx in CSF (e.g., direct intrathecal, intracranial, or intracerebroventricular injections, or gene expression in damaged tissue resulting in Hx exposed to CSF).
The patient population defined by “subject in need thereof” is any subject that has had a hemorrhagic stroke (a.k.a., “brain hemorrhage”, “cerebral hemorrhage”, or “intracranial hemorrhage”), because such patients are “in need thereof” of treatment or prevention of “adverse secondary neurological outcomes”.
The phrase “therapeutically effective amount hemopexin (Hx)” is understood to be at least any amount ranging from “about 2 µM to about 1 mM” (see, e.g., Spec. filed 8/01/2023 at 29 at lines 5-30).
The phrase “for a period of time sufficient to allow the Hx to form a complex with, and thereby neutralize, the cell-free heme” is not defined in the Specification, but is understood to merely impart that treatment takes a non-zero amount of time, and that treatment occurs when Hx complexes with cell-free-heme. This phrase is therefore deemed to be inherently, implicitly, or inherently satisfied if the treatment is functional or if art teaches that Hx binds to heme (i.e., the binding takes a non-zero amount of time).
Accordingly, the active method steps are understood to be satisfied by is understood to be fully satisfied by any prior art embodiments that satisfy the active steps of administering “about 2 µM to about 1 mM” of hemopexin to the CSF of a patient that has had a hemorrhagic stroke (a.k.a., “brain hemorrhage”, “cerebral hemorrhage”, or “intracranial hemorrhage”), permitting the hemopexin to bind to heme.
Regarding the clause stating “and thereby neutralise, the cell-free heme” at claim 1: Per MPEP § 2111.04(I), “Claim scope is not limited by claim language that . . . . does not require steps to be performed, or by claim language that does not limit a claim to a particular structure”, and further states that a “whereby clause” in a claim “is not given weight when it simply expresses the intended result of a process step positively recited”. Here, the “wherein” clause does not unambiguously correspond to a clear structure/function relationship in the original disclosure, and therefore is not a functional limitation. Rather, the “wherein” clause is understood to merely recite an intended or expected result fully satisfied by the positively recited steps and/or structures set forth in the body of the claim. Therefore, the “wherein” clause of “and thereby neutralise, the cell-free heme” is understood to be fully satisfied by all prior art embodiments that satisfy the active steps of administering “about 2 µM to about 1 mM” of hemopexin to the CSF of a patient that has had a hemorrhagic stroke (a.k.a., “brain hemorrhage”, “cerebral hemorrhage”, or “intracranial hemorrhage”), permitting the hemopexin to bind to heme.
The term “about” is undefined on record. The term “about” is given its ordinary meaning in view of the biochemical arts, and is understood to mean “within 20 percent” (see, e.g., US 2009/0028832 A1 at ¶[0111]; see also US 2009/0105341 A1 at ¶[0049]; see also US 2012/0178676, at ¶[0277]). Accordingly, with respect to the instant disclosure and with prior art of record, unless the term “about” is otherwise clearly defined, the term is reasonably inferred to indicate a range either “within 20 percent” of a recited number.
Regarding instant claim 5: Claim 5 depends from claim 1, wherein claim 1 encompasses prophylactic treatment (i.e., “treating or preventing”). Accordingly, claim 5 is understood to recite an intended outcome that would necessarily follow from the completion of the active method steps recited within the body of instant claim 1, rather than a required limitations further limiting the patient population.
Additional claim interpretations are discussed below.
Objections to the Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see Spec. filed 8/01/2023 at 87 at lines 1-5 and lines 25-35, page 88 at lines 1-10). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Drawings
The drawings are objected to under 37 CFR 1.83(a) because Figure 1 does not show yellow, blue, violet, or green (see Spec. filed 8/01/2023 at 75 at lines 9-21) and Figure 2 does not show blue or red (see Spec. filed 8/01/2023 at 6 at lines 10-14) as described in the specification. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Objections to the Claims
Claim 1 is objected to because of the following informalities:
Claim 1 contains grammatical errors, namely the recitation of “the CSF of a the subject”, which contains the definite and indefinite articles consecutively.
Claim 1 contains grammatical errors, namely the phrase “a therapeutically effective amount hemopexin (Hx)” should be “a therapeutically effective amount of hemopexin (Hx)”
Appropriate correction is required.
Claim Rejections
Claim Rejections - 35 USC § 112(b)
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 11 and 19 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.
Claim 11 recites the indefinite range of “within about 21 days”, which conflates qualitative and quantitative language. The range of “within” 21 days is 0 to <21, and “about 21 days” is unclear, but presumably ±4 days. This is pertinent because it is unclear if 22 days, 23, days, 24 days, or 25 days is included or excluded by the claim scope, since such durations are “about 21 days”, but not “within” 21 days. For purposes of applying prior art, “about” is applied prior to “within”, such that the limitation is interpreted as within [21±4] days. Furthermore, it is understood that hemopexin is naturally present in tissue and blood at the time of the ICH, which would mean hemopexin is exposed to CSF upon ICH.
Claim 19 recites the indefinite range of “at least about 2 minutes”, which conflates qualitative and quantitative language. The range of “at least” 2 minutes includes anything over 2 minutes; but “about 2” presumably encompasses 2 ±0.4 minutes. This is pertinent because it is unclear if 1.5, 1.6, 1.7, 1.8, 1.9 or 1.99 minutes is included or excluded by the claim scope, since such durations are “about” 2 minutes, but not “at least” 2 minutes. For purposes of applying prior art, “about” is applied prior to “at least”, such that the limitation is interpreted as within “at least [2.0±0.4] minutes” or “at least 1.6 minutes”.
Accordingly, claims 11 and 19 are rejected.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
[Prior Art Rejection 01]
Claims 1-2, 5, 11, 13, 19, and 22 are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Yang et al.1.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
Regarding claims 1-2, Yang reduces to practice a method of treating a subject after intracerebral hemorrhage (i.e., traumatic hemorrhage, surgically introduced) by administering to the right caudate nucleus of the brain (i.e., an intracranial injection) 0.25 mg hemopexin in 50µL2, wherein such treatment necessarily exposed CSF to both blood and hemopexin (i.e., it is an ICH model) for a time sufficient to successfully reduce encephalaedema in the brain tissue (see, e.g., Yang at title, abs at § Objective, abs at § Results, abs at § Conclusion). Regarding claim 5, Yang explicitly identifies that treatment reduced encephalaedema (oedema in the brain tissue) (see, e.g., Yang at title, abs at § Objective, abs at § Results, abs at § Conclusion). Regarding claim 11, exposure of CSF to administered Hx is understood to occur immediately upon occurrence of the intracerebral injection of blood and hemopexin (see id). This is well “within about 21 days” of the onset of the hemorrhage. Regarding claim 13, hemopexin was administered by injection to the right caudate nucleus of the brain, which is an intracranial injection (see id). Regarding claim 19, the period of time to which CSF was exposed to Hemopexin is not specified, but the CSF:Hx exposure would last for the duration of healing, and the experiment continued for 1-21 days (see, e.g., Yang at title, abs at § Results, abs at § Conclusion). Therefore, while not specified, it is understood that the CSF:Hx exposure necessarily and inherently lasted substantially longer than “at least about 2 minutes”. Regarding claim 22, Yang reduces to practice a method of treating a subject after intracerebral hemorrhage (i.e., traumatic hemorrhage, surgically introduced) by administering to the right caudate nucleus of the brain (i.e., an intracranial injection) 0.25 mg hemopexin in 50µL3 (see, e.g., Yang at title, abs at § Objective, abs at § Results, abs at § Conclusion), which is understood to be approximately 83.3 µM, and therefore well-within the recited “therapeutically effective amount” at instant claim 22.
Accordingly, claims 1-2, 5, 11, 13, 19, and 22 are anticipated by the prior art.
[Prior Art Rejection 02]
Claims 1-2, 5, 11, and 19 are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Leclerc et al4.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
Leclerc pertains to methods of reducing secondary injuries following intracerebral hemorrhages (ICH) (e.g., inflammation, edema, neurotoxicity) by increasing the level of brain hemopexin in subjects (see, e.g., Leclerc at title, abs, 1032 at col I-II at § introduction). Leclerc concludes that “These novel findings provide evidence for the use of exogenous locally administered Hpx as a potential therapeutic for ICH” (see, e.g., Leclerc at abs, 1045 at col I at 1st full ¶). Regarding instant claim 1, Leclerc teaches and reduces to practice a method of treating or preventing adverse secondary outcomes in a striatal mouse model of intracerebral hemorrhage (ICH) (see, e.g., Leclerc at 1035 at col I at § ICH model, Fig. 5 on 1042, referring to “site of injury (striatum)”), by administering rAAV1-Hpx to mice (“Hpx mice”) via bilateral intracerebroventricular injection (see, e.g., Leclerc at 1034 at col I at § rAAVI injection, 1035 at col I at § ICH model), wherein the rAAV1-Hpx caused hemopexin to be expressed within the brain tissue of the mice at approximately 60-fold normal levels (see, e.g., Leclerc at 1037 at Fig. 1, 1038 at Fig. 2, 1036 at col II to 1037 at col II at bridging ¶, 1041-1042 at bridging ¶). The mice with increased hemopexin showed improved anatomical and functional outcomes following ICH (see, e.g., Leclerc at 1038 at col I at § “High local Hpx levels improve anatomical and functional outcomes following ICH” to 1039 col I at 1st partial ¶. 1039 at Fig. 3), including reduced perihematomal tissue injury (see id) and decreased astrogliosis and microgliosis (see, e.g., Leclerc at 1041 at col I 2nd ¶ to final ¶). Leclerc states that
Thus, the highly over expressed and secretory Hpx is perfectly positioned to bind and neutralize extracorpuscular heme released by hemolysis occurring within the hematoma, thereby potentially protecting surrounding viable brain tissue from secondary heme-mediated damage.
(see, e.g., Leclerc at 1043 at col I-II at bridging ¶).
Accordingly, Leclerc teaches, discloses, and reduces to practice a model system wherein Hpx is administered via rAAV to ICH patients at a therapeutically effective concentration, and for a period of time sufficient to achieve therapeutically beneficial outcomes, understood to be mediated by the reaction of hemopexin with free heme. Regarding instant claim 2, Leclerc is understood to utilize a mouse model of a traumatic hemorrhage (surgically-induced trauma) that models intracerebral hemorrhage (ICH) (see, e.g., Leclerc at 1035 at col I at § ICH model, Fig. 5 on 1042, referring to “site of injury (striatum)”). Regarding instant claim 5, Leclerc identifies that the mice with increased hemopexin showed improved anatomical and functional outcomes following ICH (see, e.g., Leclerc at 1038 at col I at § “High local Hpx levels improve anatomical and functional outcomes following ICH” to 1039 col I at 1st partial ¶. 1039 at Fig. 3), including reduced perihematomal tissue injury (see id) and decreased astrogliosis and microgliosis (see, e.g., Leclerc at 1041 at col I 2nd ¶ to final ¶), and smaller hematoma volumes (see, e.g., Leclerc at 1045 at col I at 1st partial ¶). Accordingly, an artisan would readily appreciate that increased levels of Hpx treated or prevented at least neurotoxicity, inflammation, and oxidative tissue injury to an extent supporting Leclerc’s conclusions that “These novel findings provide evidence for the use of exogenous locally administered Hpx as a potential therapeutic for ICH” (see, e.g., Leclerc at abs, 1045 at col I at 1st full ¶; see also id. at 1041 at col I at 1st full ¶). Regarding claims 11 and 19, the Hx was expressed within the tissues (see, e.g., Leclerc at 1034 at col I at § rAAVI injection, 1035 at col I at § ICH model), wherein the rAAV1-Hpx caused hemopexin to be expressed within the brain tissue of the mice at approximately 60-fold normal levels (see, e.g., Leclerc at 1037 at Fig. 1, 1038 at Fig. 2, 1036 at col II to 1037 at col II at bridging ¶, 1041-1042 at bridging ¶). Accordingly, such expressed Hemopexin would have been exposed to CSF beginning immediately upon the tissue damage utilized in the ICH model, and the expressed hemopexin would be “exposed” to CSF for the duration of healing, wherein the experiment lasted at least 72 hours (see, e.g., Leclerc at 1035 at col I-II at § Tissue and biospecimen harvesting).
Accordingly, claims 1-2, 5, 11, and 19 are anticipated by the prior art.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
[Prior Art Rejection 03]
Claims 13 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Leclerc et al5 as applied to claims 1-2, 5, 11, and 19 above, and further in view of Dong et al6 and Hugelshofer et al.7 and Yang et al.8.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
Regarding claims 1-2, 5, 11, and 19, the teachings of Leclerc as applied to claims 1-2, 5, 11, and 19 have been discussed above, and those teachings are incorporated herein. In sum, Leclerc teaches and discloses methods of reducing secondary injuries following intracerebral hemorrhages (ICH) (e.g., inflammation, edema, neurotoxicity) by increasing the level of brain hemopexin in subjects (see, e.g., Leclerc at title, abs, 1032 at col I-II at § introduction). Leclerc administers hemopexin via rAAV expression, and shows that raising hemopexin to levels of 60-fold of normal levels produced therapeutic benefits9.
The primary reference differs from instant claims 13, 22, and the elected species as follows: Leclerc does not explicitly reduce to practice a method of treating an intracerebral hemorrhage by directly injecting hemopexin into the brain (e.g., intracranially, intracerebroventricularly, etc.) at “about 2 µM to about 1 mM” with an infusion rate of approximately 100 nl/s for approximately 5 minutes.
Leclerc provides direct motivation to treat locally administer hemopexin to intracerebral hemorrhage patients at a therapeutically effective amount: Leclerc explicitly summarizes the clinical relevance and suggestions of the proffered data by concluding that “These novel findings provide evidence for the use of exogenous locally administered Hpx as a potential therapeutic for ICH” (see, e.g., Leclerc at abs, 1045 at col I at 1st full ¶). Accordingly, there was direct motivation to locally administer exogenous Hpx to ICH patients, with the reasonable expectation of successfully achieving the desirable outcomes observed by Leclerc.
Administration routes and methodologies for directly and locally administering hemopexin and other heme-scavenging proteins to brain tissue were already known and practiced in the art: In view of the direct suggestion to locally administer exogenous Hpx to ICH patients by Leclerc (see preceding paragraph), an artisan would review available art pertinent to (i) delivering hemopexin to the brains of patients for other conditions, or otherwise (ii) delivering other heme-scavenging proteins to the brains of brain hemorrhage patients. Such review would readily lead an artisan to Dong, Hugelshofer, and Yang:
Dong pertains to the use of hemopexin to treat cognitive dysfunction in cerebral ischemia-reperfusion injuries (see, e.g., Dong at title, abs); Dong explicitly teaches and exemplifies methods of directly administering exogenous hemopexin via a specific type of intracranial injection, namely via intracerebroventricular injection, at 1.86 g/l10 at a rate of approximately 3.3 µl/min11 within 3 minutes, and the needle was left in place for five additional minutes12 (see, e.g., Dong at 2 at col II at § Intracerebroventricular injection).
Hugelshofer pertains to the administration of haptoglobin, which is a scavenging protein like hemopexin, and Hugelshofer discloses a method of directly administering the therapeutic scavenging protein to brain hemorrhage patients via a type of intracranial injection (i.e., subarachnoid injection to the cisterna chiasmatica) 10 µl of Haptoglobin at 1 mM13 at an infusion rate of 100 nl/s (see, e.g., Hugelshofer at Supp. at 8-9 at § Mouse Model), and the needle was left in place for five minutes (see id). An artisan would readily appreciate that such administration methodology could be utilized with another scavenging protein taught for use in treating brain hemorrhage patients, such as hemopexin.
Yang reduces to practice a method of treating a subject after intracerebral hemorrhage (i.e., traumatic hemorrhage, surgically introduced) by administering to the right caudate nucleus of the brain (i.e., an intracranial injection) 0.25 mg hemopexin in 50µL14, wherein such treatment necessarily exposed CSF to both blood and hemopexin (i.e., it is an ICH model) for a time sufficient to successfully reduce encephalaedema in the brain tissue (see, e.g., Yang at title, abs at § Objective, abs at § Results, abs at § Conclusion).
Accordingly, one of ordinary skill in the hemoplexin and brain hemorrhage arts would readily appreciate (i) how to locally deliver a protein, such as hemopexin, directly to the brain of a subject (e.g., intracranial injections, intracerebroventricular injection, ubarachnoid injection to the cisterna chiasmatica) (compare id. with instant claim 13); (ii) what concentrations to utilize for such proteins to be therapeutically effective (e.g., ~31µM to 83.3µM, and up to at least 1 mM) (compare id. with instant claim 22; see, e.g. MPEP § 2144.05(I), noting that “in the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists”); and (iii) what infusion rate to utilize for protein delivery for safety (e.g., 3.3 µl/min15 up to at least 100 nl/s) (compare id. with elected species; see, e.g. MPEP § 2144.05(I), noting that “in the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists”). Accordingly, following the direct guidance of the primary reference to “use [] exogenous locally administered Hpx as a potential therapeutic for ICH” (see, e.g., Leclerc at abs, 1045 at col I at 1st full ¶), an artisan would readily appreciate what types of injection routes, concentrations, and infusion rates would have a reasonable expectation of successfully treating ICH using exogenous locally administered Hpx.
The expected and predicted results of such direct and localized administration were known in the prior art: The outcome of using “exogenous locally administered Hpx as a potential therapeutic for ICH” (see, e.g., Leclerc at abs, 1045 at col I at 1st full ¶), is addressed in the prior art. Specifically, Leclerc states that
Thus, the highly over expressed and secretory Hpx is perfectly positioned to bind and neutralize extracorpuscular heme released by hemolysis occurring within the hematoma, thereby potentially protecting surrounding viable brain tissue from secondary heme-mediated damage.
(see, e.g., Leclerc at 1043 at col I-II at bridging ¶).
Accordingly, hemopexin would be expected to neutralize extracorpuscular heme released by hemolysis upon ICH, which would be expected to product surrounding brain tissue from “secondary heme-mediated damage” (see id.), which would be understood to include at least neurotoxicity, inflammation, and oxidative tissue injury (see, e.g., Leclerc at abs, 1045 at col I at 1st full ¶; see also id. at 1041 at col I at 1st full ¶), as well as reducing encephalaedema in the brain tissue (see, e.g., Yang at title, abs at § Objective, abs at § Results, abs at § Conclusion).
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): It would have been obvious to combine prior art elements (i.e., hemopexin, known methods of intracranially injecting proteins at known concentration ranges) according to known methods of treating patients with intracerebral hemorrhages (ICH), to predictably and expectedly reduce secondary injuries following an ICH that are associated with extracorpuscular heme released by hemolysis, exactly as taught and suggested by the prior art (see, e.g., MPEP §§ 2143(I)(A), (C), (D), (F), and (G)).
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to follow direct guidance provided by the primary reference (i.e., to locally administer hemopexin to treat ICH patients) by simply using known concentrations, infusion rates, and administration routes known in the prior art, in order to achieve the exact outcomes taught by the prior art (e.g., reduction of secondary injuries associated with ICH and cell-free heme).
Accordingly, claims 13 and 22 are rejected.
[Prior Art Rejection 04]
Claims 1-2, 5, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/03026216 (Feb. 14, 2019; cited in IDS filed 3/07/2024 as Cite No. 10).
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
Regarding instant claims 1-2, 5, 11, 19, and 22, WO’262 discloses and claims a method of treating a condition associated with hemolysis, including haemorrhagic stroke and intracranial haemorrhages (ICH), by administering to a subject in need thereof a liquid formulation comprising hemopexin (see, e.g., WO’262 at claims 1, 28, 36, 38 and 40; see also WO’262 at page 32 at lines 9-35). Regarding claims 1 and 5, and recitations of intended and expected results, Per MPEP § 2111.04(I), “Claim scope is not limited by claim language that . . . . does not require steps to be performed, or by claim language that does not limit a claim to a particular structure”, and further states that a “whereby clause” in a claim “is not given weight when it simply expresses the intended result of a process step positively recited”. Here, the prior art of WO’262 explicitly teaches and claims methods of administering the same compound to the same patient population for the explicit purpose of treating conditions associated with hemolysis (see, e.g., WO’262 at claims 1, 28, 36, 38 and 40; see also WO’262 at page 32 at lines 9-35), which would necessarily encompass heme-related biological processes, including toxicity caused by oxidation of membrane components and the promotion of cell lysis and death (see, e.g., WO’262 at claims 1, 28, 36, 38 and 40, page 1 at lines 22-35). Furthermore, WO’262 explicitly teaches that such treatment would ameliorate heme-induced inflammation and oxidative injuries (see, e.g., WO’262 at claims 1, 28, 36, 38 and 40, page 2 at lines 27-35). Accordingly, the intended and expected results recited at claims 1 and 5 would be understood to necessarily occur upon following the guidance of the prior art and administering hemopexin to patients in need of treatment for haemorrhagic stroke and intracranial haemorrhages (ICH) (see, e.g., WO’262 at claims 1, 28, 36, 38 and 40; see also WO’262 at page 32 at lines 9-35). Regarding claim 11, WO’262 claims methods of treatment for haemorrhagic stroke and intracranial haemorrhages (ICH) (see, e.g., WO’262 at claims 1, 28, 36, 38 and 40; see also WO’262 at page 32 at lines 9-35), and therefore treatment would presumably commence immediately upon diagnosis (i.e., within 21 days).
WO’262 differs from the instant claims as follows: Although WO’262 explicitly teaches, claims, and directs artisans to administer hemopexin to patients having haemorrhagic stroke or intracranial haemorrhages (ICH) to treat conditions associated with hemolysis. WO’262 does not reduce to practice an example of such treatment.
Although not reduced to practice, WO’262 discloses and claims a method of treating a condition associated with hemolysis, including haemorrhagic stroke and intracranial haemorrhages (ICH), by administering to a subject in need thereof a liquid formulation comprising hemopexin (see, e.g., WO’262 at claims 1, 28, 36, 38 and 40; see also WO’262 at page 32 at lines 9-35). Accordingly, an artisan would have direct guidance and motivation to practice such methods with a reasonable expectation of success.
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): It would have been obvious to combine prior art elements (e.g., hemopexin) according to known methods of treating conditions associated with hemolysis, including haemorrhagic stroke and intracranial haemorrhages (ICH), by administering to a subject in need thereof a liquid formulation comprising hemopexin, exactly as taught, suggested, claimed, and disclosed by the prior art, wherein such treatment would predictably and expectedly reduce hemolysis-associated injuries including heme-related toxicity, heme-induced inflammation and heme-induced oxidative injuries (see, e.g., MPEP §§ 2143(I)(A) and (G)).
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to follow direct guidance provided by the primary reference (i.e., to administer hemopexin to treat ICH patients) to achieve the exact outcomes taught by the prior art.
Claims 1-2, 5, and 11 are rejected.
[Prior Art Rejection 05]
Claims 13, 19, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/03026217 (Feb. 14, 2019; cited in IDS filed 3/07/2024 as Cite No. 10) as applied to claims 1-2, 5, and 11 above, and further in view of Dong et al18 and Yang et al.19.
Claim interpretation: The applicable claim interpretation has been set forth in a preceding section above, and those interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
The teachings of WO’262 as applied to claims 1-2, 5, and 11 have been discussed above, and are incorporated into the instant rejection.
The primary reference differs from instant claims 13, 19, and 22 as follows: WO’262 does not explicitly teach intracranial administration of hemopexin at “about 2 µM to about 1 mM”.
However, in view of the guidance regarding WO’262 (see, e.g., WO’262 at claims 1, 28, 36, 38 and 40; see also WO’262 at page 32 at lines 9-35), an artisan attempting to treat ICH by administering hemopexin would review the prior art for known and relevant guidance regarding delivery routes and concentration required.
Administration routes and methodologies for directly and locally administering hemopexin to brain tissue were already known and practiced in the art: In view of the guidance of the primary reference, an artisan would review available art pertinent to delivering hemopexin to the brains of patients for the same or similar conditions. Such review would readily lead an artisan to Dong and Yang:
Dong pertains to the use of hemopexin to treat cognitive dysfunction in cerebral ischemia-reperfusion injuries (see, e.g., Dong at title, abs); Dong explicitly teaches and exemplifies methods of directly administering exogenous hemopexin via a specific type of intracranial injection, namely via intracerebroventricular injection, at 1.86 g/l20 at a rate of approximately 3.3 µl/min21 within 3 minutes, and the needle was left in place for five additional minutes22 (see, e.g., Dong at 2 at col II at § Intracerebroventricular injection).
Yang reduces to practice a method of treating a subject after intracerebral hemorrhage (i.e., traumatic hemorrhage, surgically introduced) by administering to the right caudate nucleus of the brain (i.e., an intracranial injection) 0.25 mg hemopexin in 50µL23, wherein such treatment necessarily exposed CSF to both blood and hemopexin (i.e., it is an ICH model) for a time sufficient to successfully reduce encephalaedema in the brain tissue (see, e.g., Yang at title, abs at § Objective, abs at § Results, abs at § Conclusion).
Accordingly, one of ordinary skill in the hemoplexin and brain hemorrhage arts would readily appreciate how to locally deliver hemopexin directly to the brain of a subject via intracranial injection (compare with instant claim 13), and would appreciate what concentrations to utilize for such proteins to be therapeutically effective (e.g., ~31µM to 83.3µM) (compare with instant claim 22; see, e.g. MPEP § 2144.05(I), noting that “in the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists”). Accordingly, following the direct guidance of the primary reference, and artisan would perform the claimed methodology of treating haemorrhagic stroke and intracranial haemorrhages (ICH), by intracranially administering to such patients 31µM to 83.3µM of hemopexin, with the reasonable expectation of successfully treating hemolysis-induced and heme-induced issues (e.g., inflammation, tissue toxicity, etc.). Regarding claim 19, Dong identifies that hemopexin naturally occurs in brain tissue (see Dong at 1-2 at bridging ¶, 2 at col I at 1st full ¶, and therefore upon ICH it would be reasonably understood that hemopexin would necessarily be exposed to CSF for the duration of healing required. In addition, or alternatively, Dong explicitly teaches a 3 minute infusion time (see, e.g., Dong at 2 at col II at § Intracerebroventricular injection), and therefore hemopexin would be “exposed” to CSF for at least those three minutes.
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s): It would have been obvious to combine prior art elements (e.g., hemopexin) according to known methods of treating conditions associated with hemolysis, including haemorrhagic stroke and intracranial haemorrhages (ICH), by administering via intracranial injection ~31µM to ~83.3µM of hemopexin to patients as suggested by Dong and Yang, wherein such treatment would predictably and expectedly reduce hemolysis-associated injuries including heme-related toxicity, heme-induced inflammation and heme-induced oxidative injuries as taught and suggested by the primary reference (see, e.g., MPEP §§ 2143(I)(A) and (G)).
No evidence of unexpected results commensurate in scope with the requirements of MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to follow direct guidance provided by the primary reference (i.e., to administer hemopexin to treat ICH patients) to achieve the exact outcomes taught by the prior art.
Claims 13, 19, and 22 are rejected.
Claim Rejections - 35 USC § 112(a), Scope of Enablement
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, 5, 11, 13, 19, and 22 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”, does not reasonably provide enablement for “preventing”. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to “prevent” all adverse secondary neurological outcomes in a subject following a haemorrhagic stroke. The invention commensurate in scope with these claims.
The applicable legal standards for enablement are discussed at MPEP § 2164 and the specific legal standards relevant to determinations regarding the scope of enablement are set forth at MPEP § 2164.08. MPEP § 2164 identifies the following relevant factors for determining “undue” experimentation: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.” The factors which have led the Examiner to conclude that the specification fails to teach how to make and/or use the claimed invention without undue experimentation, are addressed in detail below.
Claim 1 is representative of the pending claims. The claim scope broadly claims a method of “preventing” all adverse secondary neurological outcomes in a subject following a haemorrhagic stroke. Accordingly, the invention pertains to a medical intervention, and therefore one of ordinary skill in the art would be a medical practitioner or a medical researcher.
The scope of the claim is vast and problematic because there are numerous “adverse secondary neurological outcomes” associated with hemorrhagic stroke, including, for example, “brain death” (see, e.g., Naidech24 at title, abs). In addition, secondary injuries would include perihematomal edema, iron toxcicity and oxidative stress, inflammation, apoptosis, etc., etc., which are processes that rapidly progress immediately at the time of the injury. Therefore, it is not credible to assume, without any objective supporting evidence, that all such secondary neurological outcomes could be wholly “prevented” in the absence of objective supporting evidence establishing that injection of hemopexin in a patient after the occurrence of a hemorrhagic stroke could actually “prevent” secondary injuries.
Critically, the record provides zero evidence that any adverse secondary neurological outcomes in a subject following a haemorrhagic stroke can be entirely “prevented” by administering hemopexin in a patient that has had a haemorrhagic stroke, as presently claimed. Zero evidence that inflammation, brain death, edema, apoptosis, etc. can be “prevented” has been placed on record. Similarly, no cited art of record identifies that all adverse secondary neurological outcomes can be “prevented”, only treated.
At best, the data of record shows that a traumatic brain hemorrhage caused by injecting aqueous hemopexin ameliorates and reduces (i.e., treats) secondary injuries associated with brain hemorrhage better than a control (see Spec. filed 8/01/2023 at Example 3 at 83-85). Zero evidence of “preventing” all secondary injuries was shown.
This lack of evidence does not address concerns raised in the prior art, because secondary injuries can occur from multiple, complex, and intertwined pathways that are not dependent only upon cell-free heme upon RBC lysis:
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(see, e.g., Babu25 at title, abs, Fig. 1 at 2, reproduced in part above). The art teaches that “the majority of the brain injury due to ICH typically occurs within the first few hours” (see, e.g., Babu at 1 at col II to page 2 at col I at bridging ¶, Fig. 3 on 4). No evidence that such secondary injuries can be “prevented” from occurring.
In the absence of credible, objective supporting evidence, an artisan would not reasonably conclude that all secondary injuries were preventable in all haemorrhagic stroke patients commensurate in scope with the instant claims. Furthermore, an artisan would be unduly required to newly invent or discover means to prevent secondary injuries from occurring by somehow administering a drug after such injuries had already been initiated in order to fully enable the pending claim scope, and otherwise discover ways to prevent brain death and other secondary injuries after haemorrhagic stroke by administering hemopexin. Given the inability to reverse time or death, an artisan would not reasonably or credibly think such outcomes were possible. Rather, an artisan would believe and conclude that, at best, treatment of a patient that had already suffered a haemorrhagic stroke would lead to amelioration of existing secondary injuries related to cell-free heme and thereby minimize injuries from compounding.
Therefore, in view of the lack of guidance and working examples, and failure to address the concerns present in the art, an artisan would be unduly burdened to practice the full scope of the instantly claimed invention.
Accordingly, claims 1-2, 5, 11, 13, 19, and 22 are rejected. This rejection could be overcome by amended claim 1 to remove “or preventing” at line 1.
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.
[NSDP Rejection 01]
Claims 1-2, 5, and 11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 19, 27, 29, and 31 of U.S. Patent No. 12.396,943. Although the claims at issue are not identical, they are not patentably distinct from each other as described below.
MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis (see, e.g., MPEP § 804(II)(B)(2)-(3)). The following rejection is based upon an anticipation analysis.
Regarding instant claims 1-2, 5, and 11, US’943 claims a method of treating hemorrhagic stroke and intra-cranial hemorrhage (ICH) by administering to a subject hemopexin, with the expected and predicted outcome of treating hemolysis-associated conditions (see, e.g., US’943 at claims 1, 19, 27, 29, and 31), wherein “conditions associated with hemolysis” would be understood to include heme-induced inflammation and oxidative injuries (see, e.g., US’943 at col I at lines 33-55; see, e.g., MPEP § 804(II)(B)(1), noting that it is permissible to use the specification as a dictionary to learn the meaning of a term in a claim). Notably, the limitations recited at instant claims 2, 5, and 11 do not patentably distinguish the claim scopes at issue.
Regarding claims 1 and 5, and recitations of intended and expected results, Per MPEP § 2111.04(I), “Claim scope is not limited by claim language that . . . . does not require steps to be performed, or by claim language that does not limit a claim to a particular structure”, and further states that a “whereby clause” in a claim “is not given weight when it simply expresses the intended result of a process step positively recited”. Here, the issued claims explicitly teach and direct administering the same compound to the same patient population for the explicit purpose of treating conditions associated with hemolysis (see, e.g., US’943 at claims 1, 19, 27, 29, and 31). Accordingly, the same active method steps using the same compound upon the same patient population is being claimed, which would necessarily lead to the same result.
Regarding claim 11, WO’262 claims methods of treatment for haemorrhagic stroke and intracranial haemorrhages (ICH) (see, e.g., US’943 at claims 1, 19, 27, 29, and 31), and therefore treatment would presumably commence immediately upon diagnosis and commencement of treatment (i.e., within 21 days).
Accordingly, claims 1-2, 5, and 11 are not patentably distinct from the issued claims.
[NSDP Rejection 02]
Claims 1-2, 5, 11, 13, 19, and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 19, 27, 29, and 31 of U.S. Patent No. 12,396,943 and in view of Dong et al26 and Yang et al.27.
MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis (see, e.g., MPEP § 804(II)(B)(2)-(3)). The following rejection is based upon an obviousness analysis.
The analysis of US’943 to instant claims 1-2, 5, and 11 have been discussed above under an anticipation analysis, and those teachings are incorporated herein. Anticipation is the epitome of obviousness.
US’943 differs from instant claims 13, 19, and 22 as follows: The primary reference claims do not explicitly recite intracranial administration of hemopexin at “about 2 µM to about 1 mM” to patients having ICH.
However, an artisan attempting to treat ICH by administering hemopexin as explicitly recited in the issued claims of US’943 would review the prior art for known and relevant guidance regarding delivery routes and concentration required. Administration routes and methodologies for directly and locally administering hemopexin to brain tissue were already known and practiced in the art: In view of the guidance of the primary reference, an artisan would review available art pertinent to delivering hemopexin to the brains of patients for the same or similar conditions. Such review would readily lead an artisan to Dong and Yang:
Dong pertains to the use of hemopexin to treat cognitive dysfunction in cerebral ischemia-reperfusion injuries (see, e.g., Dong at title, abs); Dong explicitly teaches and exemplifies methods of directly administering exogenous hemopexin via a specific type of intracranial injection, namely via intracerebroventricular injection, at 1.86 g/l28 at a rate of approximately 3.3 µl/min29 within 3 minutes, and the needle was left in place for five additional minutes30 (see, e.g., Dong at 2 at col II at § Intracerebroventricular injection).
Yang reduces to practice a method of treating a subject after intracerebral hemorrhage (i.e., traumatic hemorrhage, surgically introduced) by administering to the right caudate nucleus of the brain (i.e., an intracranial injection) 0.25 mg hemopexin in 50µL31, wherein such treatment necessarily exposed CSF to both blood and hemopexin (i.e., it is an ICH model) for a time sufficient to successfully reduce encephalaedema in the brain tissue (see, e.g., Yang at title, abs at § Objective, abs at § Results, abs at § Conclusion).
Accordingly, one of ordinary skill in the hemoplexin and brain hemorrhage arts would readily appreciate how to locally deliver hemopexin directly to the brain of a subject via intracranial injection (compare with instant claim 13), and would appreciate what concentrations to utilize for such proteins to be therapeutically effective (e.g., ~31µM to 83.3µM) (compare with instant claim 22; see, e.g. MPEP § 2144.05(I), noting that “in the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists”). Accordingly, following the direct guidance of the primary reference, and artisan would perform the claimed methodology of treating haemorrhagic stroke and intracranial haemorrhages (ICH), by intracranially administering to such patients 31µM to 83.3µM of hemopexin, with the reasonable expectation of successfully treating hemolysis-induced and heme-induced issues (e.g., inflammation, tissue toxicity, etc.). Regarding claim 19, Dong identifies that hemopexin naturally occurs in brain tissue (see Dong at 1-2 at bridging ¶, 2 at col I at 1st full ¶, and therefore upon ICH it would be reasonably understood that hemopexin would necessarily be exposed to CSF for the duration of healing required. In addition, or alternatively, Dong explicitly teaches a 3 minute infusion time (see, e.g., Dong at 2 at col II at § Intracerebroventricular injection), and therefore hemopexin would be “exposed” to CSF for at least those three minutes.
Obviousness analysis: Under an obviousness analysis (see, e.g., MPEP § 804(II)(B)(3)), it is noted that the scope and content of the patent claim relative to the application claims at issue have been discussed above (see, e.g., MPEP § 804(II)(B)(3)(A)), and that the differences are that the instant claims attempt to claim a different, but materially overlapping method of treating ICH patients by administering hemopexin, and therefore would be expected to achieve the same predicted and expected outcomes (see, e.g., MPEP § 804(II)(B)(3)(B)). The difference amounts to a specific recitation of an administration route and a specific concentration for use, but such differences do not patentably distinguish the claim scope because such differences were well-known in the prior art as established by Dong and Yang. Accordingly, the present claims are directed to obvious variants of the representative claims because it is well-within the ordinary skill in the art to perform the claimed method of treating ICH by administering hemopexin as claimed by the issued claims, using administration routes and concentrations already known and shown to be effective in the prior art (see, e.g., MPEP § 804(II)(B)(3)(C)-(D); see also MPEP §§ 2143(I)(A), (G)).
As issued claims in a U.S. patent, the reference claims are presumed to satisfy all statutory requirements in the absence of evidence to the contrary.
As required at (C) of MPEP § 804(II), the rejection is not prohibited by 35 U.S.C. 121.
As noted at MPEP § 804(II)(B)(4), the reference patent and the instant Application are understood to require only a one-way test for distinctiveness.
Accordingly, instant claims 1-2, 5, 11, 13, 19, and 22 are rejected.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Graw et al.32 pertains to hemopexin therapy used to prevents acute adverse effects of resuscitation after prolonged storage of red blood cells (Graw at title, abs, passim).
Aronowski et al33 discusses selected aspects of secondary brain injury after ICH and outlines key mechanisms associated with hematoma toxicity, oxidative stress, and inflammation (see, e.g., Aronowski at title, abs, passim). In addition, it discusses the relevance of hematoma resolution processes as a target for ICH therapy and presents potential clinically relevant molecular targets that could be harnessed to treat secondary injury associated with ICH injury (see id).
Chen et al.34 identifies that hemopexin knockout mice have increased striatal injury and behavioral deficits after intracerebral hemorrhage (see, e.g., Chen at at title, abs, passim).
Li et al.35 informs artisans that a Heme-hemopexin complex attenuates neuronal cell death and stroke damage (see, e.g., Li et al. at title, abs, passim).
DongII36 pertains to and discloses that hemopexin induces neuroprotection in the rat subjected to focal cerebral ischemia (see, e.g., DongII at title, abs, passim).
YangII37 pertains to the observation that hemopexin reduces blood-brain barrier injury and protects synaptic plasticity in cerebral ischemic rats by promoting EPCs through the HO-1 pathway (see, e.g., YangII at title, abs, passim).
Poillerat et al.38 informs artisans that hemopexin acts as an inhibitor of hemolysis-induced complement activation (see, e.g., Poillerat at title, abs, passim).
Robinson et al.39, circa 2009, pertains to hemin toxicity as a preventable source of brain damage following a hemorrhagic stroke (see, e.g., Robinson at title, abs), and explicitly suggests that
Another strategy would be to infuse serum proteins into the site of the hematoma. The potential of endogenous serum proteins to protect brain cells from hemorrhagic stroke has received relatively little attention, yet the usefulness of this approach has already been demonstrated . . . . . Another serum protein of interest would be hemopexin, which provides excellent protection from the toxicity of hemin, but the amount normally present in the blood is insufficient to cope with the quantities of hemin released after a hemorrhagic stroke.
(see, e.g., Robinson at 234 at col I-II at bridging ¶, emphasis added).
Conclusion
No claims are allowed.
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/RANDALL L BEANE/ Primary Examiner, Art Unit 1654
1 Yang et al., [The Effects of the Hemopexin on Generation of Free Radicals and Brain Edema after Intracerebral Hemorrhage]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2015 Sep;46(5):717-21, 743. Chinese. PMID: 26619542. Abstract Only.
2 Hemopexin has a MW of ~60 mg/µmol. 50 uL is 0.00005L. Concentration in mg/mL = 0.25mg/0.05 mL = 5 mg/mL. (5 mg/mL)/(60 mg/µmol) is 0.0833 µmol/mL or 0.0833 mM or 83.3 µM.
3 Hemopexin has a MW of ~60 mg/µmol. 50 uL is 0.00005L. Concentration in mg/mL = 0.25mg/0.05 mL = 5 mg/mL. (5 mg/mL)/(60 mg/µmol) is 0.0833 µmol/mL or 0.0833 mM or 83.3 µM.
4 Leclerc et al., Increased brain hemopexin levels improve outcomes after intracerebral hemorrhage. J Cereb Blood Flow Metab. 2018 Jun;38(6):1032-1046. doi: 10.1177/0271678X16679170. Epub 2016 Nov 19. PMID: 27864463; PMCID: PMC5999006; cited in IDS filed 8/01/2023
5 Leclerc et al., Increased brain hemopexin levels improve outcomes after intracerebral hemorrhage. J Cereb Blood Flow Metab. 2018 Jun;38(6):1032-1046. doi: 10.1177/0271678X16679170. Epub 2016 Nov 19. PMID: 27864463; PMCID: PMC5999006; cited in IDS filed 8/01/2023
6 Dong et al., Hemopexin alleviates cognitive dysfunction after focal cerebral ischemia-reperfusion injury in rats. BMC Anesthesiol. 2019 Jan 15;19(1):13. doi: 10.1186/s12871-019-0681-2. PMID: 30646866; PMCID: PMC6334464; hereafter “Dong”; cited in IDS filed 8/01/2023).
7 Hugelshofer et al., Haptoglobin administration into the subarachnoid space prevents hemoglobin-induced cerebral vasospasm. J Clin Invest. 2019 Dec 2;129(12):5219-5235 and 18 pages of Supp. data. doi: 10.1172/JCI130630. PMID: 31454333; PMCID: PMC6877320; hereafter “Hugelshofer”; cited in IDS filed 3/07/2024 as cite 72. Supplemental pages attached.
8 Yang et al., [The Effects of the Hemopexin on Generation of Free Radicals and Brain Edema after Intracerebral Hemorrhage]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2015 Sep;46(5):717-21, 743. Chinese. PMID: 26619542. Abstract Only.
9 See, e.g., Leclerc at 1034 at col I at § rAAVI injection, 1035 at col I at § ICH model, Fig. 5 on 1042, referring to “site of injury (striatum)”, 1037 at Fig. 1, 1038 at Fig. 2, 1036 at col II to 1037 at col II at bridging ¶, 1041-1042 at bridging ¶, 1038 at col I at § “High local Hpx levels improve anatomical and functional outcomes following ICH” to 1039 col I at 1st partial ¶, 1039 at Fig. 3, 1041 at col I 2nd ¶ to final ¶. See also, rejection above.
10 1.86 g/l of hemopexin, which has a MW of approximately ~60,000g/mol, wherein M =C/MW, is equivalent to 0.031 mM or 31µM.
11 3.3 µl/min is approximately 55 nl/s, as 1 µl is 1000 nl, so 3.3 µl/min X1000 is 3300 nl/min. Converting from minutes to seconds, one divides by 60 seconds, and 3300 nl/min divided by 60 seconds is 55 nl/s.
12 3.3 µl/min for 3 minutes is 9.9 µl of 31 µM hemopexin, which is approximately 18.41 µg of hemopexin administered.
13 With a volume of 10 µl at a concentration of 1 mM, wherein haptoglobin has a MW of ~85-100kDa (g/mol), this would be approximately 850µg to 1000 µg of haptoglobin.
14 Hemopexin has a MW of ~60 mg/µmol. 50 uL is 0.00005L. Concentration in mg/mL = 0.25mg/0.05 mL = 5 mg/mL. (5 mg/mL)/(60 mg/µmol) is 0.0833 µmol/mL or 0.0833 mM or 83.3 µM.
15 3.3 µl/min is approximately 55 nl/s, as 1 µl is 1000 nl, so 3.3 µl/min X1000 is 3300 nl/min. Converting from minutes to seconds, one divides by 60 seconds, and 3300 nl/min divided by 60 seconds is 55 nl/s.
16 This WIPO document corresponds to US 2020/0237652 and US 12,396,943 B2.
17 This WIPO document corresponds to US 2020/0237652 and US 12,396,943 B2.
18 Dong et al., Hemopexin alleviates cognitive dysfunction after focal cerebral ischemia-reperfusion injury in rats. BMC Anesthesiol. 2019 Jan 15;19(1):13. doi: 10.1186/s12871-019-0681-2. PMID: 30646866; PMCID: PMC6334464; hereafter “Dong” ; cited in IDS filed 8/01/2023
19 Yang et al., [The Effects of the Hemopexin on Generation of Free Radicals and Brain Edema after Intracerebral Hemorrhage]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2015 Sep;46(5):717-21, 743. Chinese. PMID: 26619542. Abstract Only.
20 1.86 g/l of hemopexin, which has a MW of approximately ~60,000g/mol, wherein M =C/MW, is equivalent to 0.031 mM or 31µM.
21 3.3 µl/min is approximately 55 nl/s, as 1 µl is 1000 nl, so 3.3 µl/min X1000 is 3300 nl/min. Converting from minutes to seconds, one divides by 60 seconds, and 3300 nl/min divided by 60 seconds is 55 nl/s.
22 3.3 µl/min for 3 minutes is 9.9 µl of 31 µM hemopexin, which is approximately 18.41 µg of hemopexin administered.
23 Hemopexin has a MW of ~60 mg/µmol. 50 uL is 0.00005L. Concentration in mg/mL = 0.25mg/0.05 mL = 5 mg/mL. (5 mg/mL)/(60 mg/µmol) is 0.0833 µmol/mL or 0.0833 mM or 83.3 µM.
24 Naidech et al., How patients die after intracerebral hemorrhage. Neurocrit Care. 2009;11(1):45-9. doi: 10.1007/s12028-009-9186-z. Epub 2009 Feb 6. PMID: 19199079.
25 Babu et al., C. (2012). Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage–induced secondary brain injury and as potential targets for intervention. Neurosurgical Focus FOC, 32(4), E8. https://doi.org/10.3171/2012.1.FOCUS11366
26 Dong et al., Hemopexin alleviates cognitive dysfunction after focal cerebral ischemia-reperfusion injury in rats. BMC Anesthesiol. 2019 Jan 15;19(1):13. doi: 10.1186/s12871-019-0681-2. PMID: 30646866; PMCID: PMC6334464; hereafter “Dong” ; cited in IDS filed 8/01/2023.
27 Yang et al., [The Effects of the Hemopexin on Generation of Free Radicals and Brain Edema after Intracerebral Hemorrhage]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2015 Sep;46(5):717-21, 743. Chinese. PMID: 26619542. Abstract Only.
28 1.86 g/l of hemopexin, which has a MW of approximately ~60,000g/mol, wherein M =C/MW, is equivalent to 0.031 mM or 31µM.
29 3.3 µl/min is approximately 55 nl/s, as 1 µl is 1000 nl, so 3.3 µl/min X1000 is 3300 nl/min. Converting from minutes to seconds, one divides by 60 seconds, and 3300 nl/min divided by 60 seconds is 55 nl/s.
30 3.3 µl/min for 3 minutes is 9.9 µl of 31 µM hemopexin, which is approximately 18.41 µg of hemopexin administered.
31 Hemopexin has a MW of ~60 mg/µmol. 50 uL is 0.00005L. Concentration in mg/mL = 0.25mg/0.05 mL = 5 mg/mL. (5 mg/mL)/(60 mg/µmol) is 0.0833 µmol/mL or 0.0833 mM or 83.3 µM.
32 Graw et al., Haptoglobin or Hemopexin Therapy Prevents Acute Adverse Effects of Resuscitation After Prolonged Storage of Red Cells. Circulation. 2016 Sep 27;134(13):945-60. doi: 10.1161/CIRCULATIONAHA.115.019955. Epub 2016 Aug 11. PMID: 27515135; PMCID: PMC5039096.
33 Aronowski et al. Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke. 2011 Jun;42(6):1781-6. doi: 10.1161/STROKEAHA.110.596718. Epub 2011 Apr 28. PMID: 21527759; PMCID: PMC3123894
34 Chen et al., Increased striatal injury and behavioral deficits after intracerebral hemorrhage in hemopexin knockout mice. J Neurosurg. 2011 Apr;114(4):1159-67. doi: 10.3171/2010.10.JNS10861. Epub 2010 Dec 3. PMID: 21128737; PMCID: PMC3061252; hereafter “Chen”.
35 Li et al., Heme-hemopexin complex attenuates neuronal cell death and stroke damage. J Cereb Blood Flow Metab. 2009 May;29(5):953-64. doi: 10.1038/jcbfm.2009.19. Epub 2009 Mar 11. Erratum in: J Cereb Blood Flow Metab. 2014 Apr;34(4):736. PMID: 19277051; PMCID: PMC6015738.
36 Dong et al., Hemopexin induces neuroprotection in the rat subjected to focal cerebral ischemia. BMC Neurosci 14, 58 (2013). https://doi.org/10.1186/1471-2202-14-58, hereafter “DongII”.
37 Yang et al., Hemopexin reduces blood-brain barrier injury and protects synaptic plasticity in cerebral ischemic rats by promoting EPCs through the HO-1 pathway. Brain Res. 2018 Nov 15;1699:177-185. doi: 10.1016/j.brainres.2018.08.008. Epub 2018 Aug 6. PMID: 30092232; hereafter “YangII”.
38 Poillerat et al., Hemopexin as an Inhibitor of Hemolysis-Induced Complement Activation. Front Immunol. 2020 Jul 31;11:1684. doi: 10.3389/fimmu.2020.01684. PMID: 32849588; PMCID: PMC7412979; hereafter “Poillerat”.
39 Robinson et al., (2009) Hemin toxicity: a preventable source of brain damage following hemorrhagic stroke, Redox Report, 14:6, 228-235, DOI: 10.1179/135100009X12525712409931
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