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 1-3, 8-12, 15-16, 18-22 are pending. Claim 1 was amended in the Reply filed 2/24/2026. Claim 16 remains withdrawn. Claims 1-3, 8-12, 15, and 18-22 are presently considered.
Election/Restrictions
Applicant’s election without traverse of the species of “enoxaparin + AT200” in the reply filed on 10/19/2022 was previously acknowledged.
The elected species was understood to corresponding to the species disclosed at Figure 3B and ¶¶[0068]-[0069] (see Reply filed 10/19/2022 at 2; see also Requirement mailed 8/24/2022 at 2), wherein the disclosed method was an ex vivo treatment of patient plasma with AT-supplemented enoxaparin (see, e.g., Spec. filed 1/12/2021 at ¶¶[0068], [0069], and Fig. 3B).
As previously noted on record, the pending claims were substantially amended in the Reply filed 11/26/2024, and were reasonably inferred to exclude the originally elected species of ex vivo treatment. The Examiner’s position was set forth in the Action mailed 1/24/20251 and was not disputed by the Applicant in the Response filed 7/23/2025. Accordingly, the amended claims as filed 2/24/2026 are understood to continue excluding the originally elected species.
As noted in the Action mailed 1/24/20252, no species set forth in the originally filed specification unambiguously reads upon the amended claim scope. Accordingly, per MPEP § 803.02(III)(A), examination has proceeded to a non-elected species, as set forth below.
Claim 16 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/19/2022.
Accordingly, claims 1-3, 8-12, 15, and 18-22 are presently examined.
Information Disclosure Statement
The IDS filed 11/25/2026 is acknowledged and presently considered.
Claim Interpretation
For purposes of examination, unless otherwise stated, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111.
Relevant claim interpretations have been set forth in previous actions of record (see, e.g., Action mailed 5/29/2024 at p. 4-11; see also Action mailed 7/21/2023 at p. 4-7; see also Action mailed 11/15/2022 at 4-7), which are incorporated herein.
Amended claim 1 is representative of the pending claim scope and is presently directed to:
1. (Currently amended) A method for reducing the occurrence of a thrombosis or a thromboembolism in a patient identified as being at risk thereof, the method comprising measuring a baseline level of antithrombin III (ATIII) in the patient and administering to the patient:
an anticoagulant selected from the group consisting of unfractionated heparin, a low molecular weight heparin, a heparinoid, fondaparinux, idraparinux, and combinations thereof, and
antithrombin III (ATIII) at 150% or more of the measured baseline level and at levels sufficient to achieve an anti-FCa level of at least 0.2 IU/ml of plasma,, wherein the ATIII is administered intravenously,
wherein the patient identified as being at risk is a blunt physical trauma patient, .
Applicable claim interpretations are set forth below.
Patient population: The applicable patient population was limited to “blunt physical trauma patient[s]” in the Reply filed 11/26/2024. The amended claim scope excludes other patient populations at risk for venous thromboembolism (VTE) (see, e.g., Spec. filed 1/12/2021 at ¶¶[0030], [0032], [0038]-[0039], [0046]-[0047]). The term “blunt physical trauma patient” does not appear in the originally filed disclosure. The term “blunt” is used with “blunt force trauma” (see, e.g., Spec. filed 1/12/2021 at ¶¶[0009], [0039]), and “blunt” is used to differentiate a subpopulation of patients from other types of “physical trauma” patients, such as patients having “penetrating trauma” (see, e.g., Spec. filed 1/12/2021 at ¶¶[0009], [0039]). The term “blunt physical trauma” is reasonably inferred to be any physical injury caused by a forceful impact without breaking the skin, including injuries caused by falls, motor vehicle collisions, physical assaults, and sports injuries; the injuries are reasonably assumed to include bruises (contusions), broken or fractured bones, concussions, and at least internal hemorrhages.
Route of administration: Amended claim 1 was explicitly limited to intravenous administration in a prior response (see, e.g., claim 1 as filed 11/26/2024). “Intravenous” administration is understood to include both “bolus and/or infusion” administrations (see, e.g., Spec. filed 1/12/2021 at ¶¶[0054]).
Timing of treatments: Claim 1 does not specify nor require that both heparin and ATIII have to be administered simultaneously, or via the same route of administration. Accordingly, the claims fully encompass prior art methods wherein patients are treated with one, and then subsequently the other, compounds as claimed.
Dosage of “anticoagulant”: The amount of “anticoagulant” administered is understood to be fully satisfied at least by the administration of low molecular weight heparin (e.g., Enoxaparin) at “a daily dose of about 20 mg to about 180 mg” 3 (see dependent claim 19) or in an amount “from about 0.1 to about 2.5 mg/kg” 4 (see dependent claim 21). Heparin is typically reported on the basis of activity, but Applicant has attempted to claim heparin by mg, and by mg/kg. Examiner notes that the typical conversion utilized is that 1 unit of heparin is equivalent to approximately 0.002 mg of pure heparin (see search notes). This typical conversion was not challenged or disputed by the Applicant in the Reply filed 5/10/2023, the Reply filed 11/26/2024, or the Reply filed 7/23/2025.
Variance of ranges: “About” is given the broadest reasonable interpretation, and is therefore understood to refer to a variance of a ±20% in a recited number (see, e.g., Spec. filed 1/12/2021 at ¶[0021]). Therefore, at instant claims 1 and 8-10 the ranges of “about . . .1.2 IU/mL”, “about…1.3”, “about…1.4”, and “about…1.5” are understood to be equivalent to the ranges of “0.96 to 1.44”, “1.04 to 1.56”, “1.12 to 1.68”, and “1.2 to 1.8”, respectively. At claims 11-12, the ranges of “about 1.2 …to about 2.5” and “about 1.5 . . .to about 2.0” are understood to be equivalent to the ranges of the minimum and maximums of “about” for each point, which is “0.96 to 3” and “1.2 to 2.4”, respectively. At claims 19-20, the ranges of “about 20 mg to about 180 mg” and “about 20 mg to about 40 mg” are understood to include “16 mg to 216 mg” and “16 mg to 48 mg”, respectively. At claims 21-22, the ranges of “about 0.1 to about 2.5” and “about 0.5 to about 1.5” are understood to be include “0.08 to 3” and “0.4 to 1.8”, respectively.
Dosage of “antithrombin III (ATIII)”: The amount of ATIII actually administered to patients has again5 been functionally limited by a result the dosage is intended to achieve subsequent to administration rather than by an actual amount of ATIII sufficient to achieve the desired and hoped for results. The result actually achieved is discernable and discoverable only after treatment is provided and infringement has occurred. Accordingly, in the absence of guidance, the functional limitation can only be achieved by foreknowledge of information obtainable only after administration occurs and it is determined whether or not ATIII was administered “at levels sufficient to achieve an anti-FXa level of at least 0.2 IU/mL of plasma”. This has again6 raised issues of indefiniteness and written description. For purposes of applying prior art to instant claims 1 and 8-12, the dosage of “antithrombin III (ATIII)” required to satisfy the functional limitations of instant claim 1 is reasonably understood to be fully satisfied by any dosage sufficient to satisfy the requirements of dependent claims 8-12 (i.e., claims 8-12 are understood to satisfy 35 USC §112(d)). Accordingly, any prior art dosage sufficient to increase a patient’s ATIII plasma levels to about or greater than 1.3 IU/mL and sufficient to satisfy claims 8-12, is understood to satisfy the functional limitation of amended claim 1. The dosage of ATIII required to satisfy the limitations of dependent claims 8-12 is understood to be “about 42 IU/kg body weight”, administered intravenously”7. This interpretation is reasonable in view of Applicant’s own prior admissions and statements (see, e.g., Reply filed 11/26/2024 at 5-6), and is fully consistent in view of the amendments previously filed 11/26/2024 identifying that administration of “about 42 IU/kg body weight” satisfied dependent claims 6-13 as filed 11/26/2024 (i.e., corresponding to instant claims 1 and 8-12) (see Action mailed 1/24/2025 at 7-8). Furthermore, this interpretation is reasonable because it is consistent with the Applicant’s own prior statements8. Accordingly, intravenous administration of ATIII at “about 42 IU/kg body weight” (i.e., 33.6 to 50.4 IU/kg of body weight) is understood to fully satisfy the functional limitations pertaining to ATIII at instant claims 1 and 8-12 for purposes of applying prior art in the instant Action.
ATIII levels naturally vary in humans: ATIII levels may naturally range from at least 0.72-1.69 IU/mL in plasma in humans (see, e.g., Dolan et al.9 at abs). This is pertinent, presumably this natural range corresponds to ATIII at “72%” up to “169%”10. Therefore, the amount of ATIII administered at claim 1 necessary to “to achieve an anti-FXa level of at least 0.2 IU/mL of plasma” as required by amended claim 1 may presumably include 0.0 IU/Kg body weight since some patients may already be at or above the functionally defined limit.
Recitations of intended or expected results at claims 2-3: Claims 2-3 are directed to intended use statements directed to the preamble of instant claim 1. Specifically, claims 2-3 do not require that the patients at issue actually suffer from VTE or venous thrombosis, but only that the treated patients be “at risk” of “the occurrence of” such things (see, e.g., MPEP § 2111.02(II)). Amended claim 1 expressly limits the claim scope to such a patient population, namely “a blunt physical trauma patient”. Accordingly, claims 2-3 do not appear to differ in scope relative to instant claim 1 since such patients would necessarily always be “at risk” of VTE.
Additional claim interpretations are set forth below.
Withdrawn Claim Rejections
The rejection of claims 1-3, 8-12, 15, and 18-22 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, are withdrawn in view of the amendments to claim 1 as filed 2/24/2026. However, a revised rejection is set forth below as necessitated by Applicant’s amendments.
The rejection of claims 1-3, 8-12, 15, and 18-22 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 is withdrawn in view of the amendments to claim 1 as filed 2/24/2026. However, a revised rejection is set forth below as necessitated by Applicant’s amendments.
The rejection of claims 1-3, 8-12, 15, and 18-22 under 35 U.S.C. 103 as being unpatentable over Sen11 and further in view of Refaei12 is withdrawn in view of the amendments to claim 1 as filed 2/24/2026. However, a revised rejection is set forth below as necessitated by Applicant’s amendments.
New or Revised Claim Rejections as Necessitated by Applicant Amendment
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 1-3, 8-12, 15, and 18-22 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.
Amended claim 1 now recites the step of “measuring a baseline level of antithrombin III (ATIII) in the patient” and then administering ATIII at “150% or more of the measured baseline level”, which renders the instant claim scope indefinite because it is well-known in the prior art that targeting a “desired level” (e.g., “150%”) is not equivalent to the actual level of ATIII achieved, and it is unknown whether this limitation is referring to a “desired level” or to an achieved level13. For example, Kowal-Vern14 pertains to the treatment of a patient having a traumatic injury and reasonably informs artisans that a baseline of ATIII levels was determined, and that an amount of ATIII was administered with the intent to “maintain the ATIII plasma level at 175%” (see, e.g., Kowal at 98 at col I at final ¶), using the formula
Amount of ATIII to achieve desired level = [(desired ATIII level % - patient ATIII level % x (admission weight, kg)] divided by 1.4
(see, e.g., Kowal at 98 at col I-II at bridging ¶). However, Kowal discloses that the “dosages calculated to achieve a level of 175%” actually caused “the ATIII levels [to reach] 203%”(see, e.g., Kowal at 100 at col I at Section 4). This evidences that a targeted and “desired ATIII level %” and the level of ATIII actually achieved may differ by at least 28%. Accordingly, the claim scope understandingly varies depending upon whether the phrase “at 150%” refers to a “desired level” of ATIII or to an actual level achieved in a patient. This is pertinent because very close prior art exists15. Accordingly, amended claim 1 is indefinite because the claim scope may be interpreted in more than one way, which yields different claim scopes, and an artisan would not be aware of how to avoid infringement. For purposes of applying prior art, it is assumed that the phrase “at 150%” refers to a “desired level” of ATIII that Applicant wishes to achieve.
Amended claim 1 now recites the step of “measuring a baseline level of antithrombin III (ATIII) in the patient” and then administering ATIII “at 150% or more of the measured baseline level”, which renders the claim scope indefinite because it is unclear how the dosage used to achieve ATIII levels “at 150% or more” is actually calculated, based on a measured baseline. More specifically, ThrombateInsert16, ATrynInsert17, and Liumbruno et al18 establish that different calculations exist for attempting to achieve a desired level of ATIII. ThrombateInsert discloses that the amount of ATIII administered should be determined using the formula
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(see, e.g., ThrombateInsert at 4 at § Dosage). However, ATrynInsert informs artisans that the amount of ATIII administered should be determined using the formulas
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(see, e.g., ATrynInsert at 1 at § Dosage, wherein “100” is understood to be a desired level of ATIII). Liumbruno discloses that antithrombin dosages are calculated using the formula
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(see, e.g., Liumbruno at 327 at col I at § Calculation of the dose of AT to administer). Accordingly, there are different, non-equivalent calculations known in the art for determining the dosage of ATIII required to achieve a “desired” ATIII level based upon a measured baseline. But the amended claim fails to clarify how a dosage required to achieve a desired level of “at 150% or more” should be determined, which fails to reasonably inform an artisan of the metes and bounds of the pending claim scope, or otherwise how to avoid infringement of the claims. Accordingly, amended claim 1 is indefinite since it is unclear how to determine how much ATIII must be administered to raise ATIII levels to 150% or more of a measured baseline, since different formulas exist and the claim provides no clarification. Accordingly, the metes and bounds of the pending claim scope are indefinite, and an artisan would not be reasonably informed of how to avoid infringement of the instantly claimed invention because very close prior art exists19. For purposes of applying prior art, intravenous administration of ATIII at “about 42 IU/kg body weight” (i.e., 33.6 to 50.4 IU/kg of body weight) is understood to fully satisfy the functional limitations pertaining to ATIII at instant claims 1 and 8-12 as explained in the claim interpretation section above20.
Amended claim 1 now recites the step of “measuring a baseline level of antithrombin III (ATIII) in the patient” and then administering ATIII at “150% or more of the measured baseline level”, which renders the instant claim scope indefinite because it is unclear what the “baseline level of antithrombin III” refers to. Moll et al.21 asks “How are Antithrombin Levels measured?” (see, e.g., Moll at 1 at § “How are Antithrombin levels Measured” to p. 2 at 1st partial ¶), and explains that
…Two different antithrombin tests can be done, (a) an antithrombin antigen level and (b) an antithrombin activity level (also called “functional test”). The antithrombin antigen test determines how much of the protein is present in the blood. The antithrombin activity test determines whether the antithrombin that is present actually works. . . .
Accordingly, the “baseline level of antithrombin III” may refer to either the “antithrombin antigen level” test and the “antithrombin activity level”, which are both used in the art, and are both “typically expressed in ‘percent’” (see id), but actually measure different aspects (i.e., ATIII protein levels overall, or functional ATIII protein). This is pertinent because the “normal” ranges of each actually differ (see, e.g., Refaei22 at 2 at col II at § 2, explaining that the reference range for immunological AT level is 0.80-1.20 U/mL, but that the reference range for functional AT levels is 0.77-1.25 U/mL). Accordingly, there are two distinct, art-recognized means of referring to a “baseline level of antithrombin III” in a patient, and it is unclear which definition is being relied upon at amended claim 1. Accordingly, the metes and bounds of the pending claim scope are indefinite, and an artisan would not be reasonably informed of how to avoid infringement of the instantly claimed invention because very close prior art exists23. For purposes of applying prior art, intravenous administration of ATIII at “about 42 IU/kg body weight” (i.e., 33.6 to 50.4 IU/kg of body weight) is understood to fully satisfy the functional limitations pertaining to ATIII at instant claims 1 and 8-12 as explained in the claim interpretation section above24.
Amended claim 1 recites the phrase “measuring a baseline level of antithrombin III (ATIII) in the patient and administering to the patient: . . . antithrombin III (ATIII) at 150% or more of the measured baseline level”, which renders the claim scope indefinite because it is unclear if the administration of ATIII is an optional step or not if the functional limitations are satisfied based upon a measured baseline. For example, the amount of ATIII naturally present in an individual varies substantially from at least 0.72-1.69 IU/mL in plasma in humans (see, e.g., Dolan et al.25 at abs; i.e., the natural range of ATIII varies from “72%” up to “169%”26); furthermore, the newly added functional limitation regarding an anti-FXa level does not unambiguously inform artisans of a minimum required amount of ATIII that must be administered, which is pertinent because the prior art shows that the administration of an anticoagulant alone (e.g., Enoxaparin) may be sufficient to achieve this outcome. For example, Tahaineh et al.27identifies that enoxaparin alone is capable achieving “an anti-FXa level of at least 0.2 IU/ml in plasma”, at some concentrations and in some patients as taught by the prior art:
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(see, e.g., Tahaineh et al. at abs, 68 at Fig. 2). Therefore, the claims raise a basic question, namely “How much, if any, ATIII should be administered to a patient that has a baseline at or above 150%?”. For example, ThrombateInsert28 discloses that the amount of ATIII administered may be determined using the formula
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(see, e.g., ThrombateInsert at 4 at § Dosage). However, if a patient already has a baseline of ATIII at 150% or above, then presumably 0 IU/kg must be administered to achieve ATIII “at 150% or above”, and the remaining functional limitation (“and at levels sufficient to achieve an anti-FXa level of at least 0.2 IU/mL of plasma”) may also be achieved by administering 0 IU/kg. Accordingly, it is unclear if the step of intravenously administering ATIII is optional depending upon the measured baseline, or if the step must always be performed even if ATIII levels are already “at 150% or more” in a patient. Accordingly, the metes and bounds of the claim scope are indefinite, because it is unclear how to perform the claimed method in view of the normal and natural ranges of ATIII, and in view of evidence showing that anti-FXa levels as claimed can be achieved in the absence of ATIII. If the step of administering ATIII is optional, then such optional steps are non-limiting (see, e.g., MPEP § 2111.04(I)), and the claim scope would potentially read upon prior art requiring administration of only an anticoagulant. Accordingly, the metes and bounds of the pending claim scope are indefinite because it is unclear if administration of ATIII is optional or required, and if required then how much should be administered. Therefore, an artisan would not be reasonably informed of how to avoid infringement of the instantly claimed invention because very close prior art exists29. For purposes of applying prior art, intravenous administration of ATIII at “about 42 IU/kg body weight” (i.e., 33.6 to 50.4 IU/kg of body weight) is understood to fully satisfy the functional limitations pertaining to ATIII at instant claims 1 and 8-12 as explained in the claim interpretation section above30.
Claims 8-12 require the administration of ATIII at an unspecified amount sufficient to achieve a functional result (e.g., claims 8-10 continue to require a dosage of ATIII sufficient to increase of the patient’s ATIII plasma levels to “about or greater than [1.3, 1.4, or 1.5] IU/mL”, respectively), which renders the scope of claims 8-12 indefinite. These functional limitations are indefinite for two reasons.
First, per MPEP § 2173.05(b)(II), references to a variable object may render a claim indefinite when the relationship between the limitation and the object is not sufficiently defined. Here, no specific administrable dosage of ATIII is disclosed as capable of achieving the claimed outcome. The amount of ATIII naturally present in an individual varies substantially from at least 0.72-1.69 IU/mL in plasma in humans (see, e.g., Dolan et al.31 at abs; i.e., the natural range of ATIII varies from “72%” up to “169%”32). Accordingly, the amount of ATIII initially administered to achieve ATIII at “about 1.3 IU/mL” or more may vary from zero in a patient with 1.69 IU/mL to >0 in a patient with 0.72 IU/mL of ATIII. This range is exemplary only, since it is reasonably understood that ATIII concentration varies from patient to patient, and therefore the relationship between the functionally defined outcome and the actual amount of ATIII required to achieve that outcome is not sufficiently defined on record, because an artisan would be unable to avoid infringement of the claim scope prior to infringing the claimed invention.
Second, per MPEP § 2173.05(g), the use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite. Here, the amount of ATIII that must be initially administered to achieve the functional outcome required by instant claims 8-12 is unknown and unspecified in the originally filed disclosure. Rather, the amount of ATIII actually administered to patients is functionally limited by reference to the outcome Applicant hopes to achieve, rather than by an unambiguous disclosure of an actual amount of ATIII sufficient to achieve the desired and hoped for result. Accordingly, whether or not a method infringes upon the claimed method is only discernable and discoverable after infringement has already occurred and the functional result already achieved, and therefore the metes and bounds of the claim scope do not permit artisans to avoid infringement. Accordingly, in the absence of clear guidance, the functional limitation can only be achieved by foreknowledge of information obtainable only after administration occurs.
These issues render the claim indefinite because, per MPEP § 2173, the purpose of 35 USC § 112(b) is to “ensure that the scope of the claims is clear so the public is informed of the boundaries of what constitutes infringement of the patent”. However, in the instant case very close prior art exists33, and the claimed functional results at claims 8-12 are reasonably inferred to be satisfied in some patients by the administration of zero IU/mL of ATIII because ATIII is naturally present in patients from at least 0.72 to 1.69 IU/mL in plasma in humans (see, e.g., Dolan et al.34 at abs; i.e., the natural range of ATIII varies from “72%” up to “169%”35). The courts have stated that
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
Here, the administered ATIII formulation only differs from the prior art presumably by the exact dosage administered to a patient, but the description of record fails to describe that dosage in a manner permitting an artisan to distinguish infringing ATIII formulations from non-infringing ATIII formulations that already exist in the prior art, and therefore “the inventor cannot lay claim to the subject matter”36. For purposes of applying prior art, intravenous administration of ATIII at “about 42 IU/kg body weight” (i.e., 33.6 to 50.4 IU/kg of body weight) is understood to fully satisfy the functional limitations pertaining to ATIII at instant claims 1 and 8-12 as explained in the claim interpretation section above.
Claims 2-3, 8-12, 15, and 18-22 depend directly or indirectly from an indefinite base claim, and fail to clarify or address the indefiniteness of the base claim. Accordingly, these claims are rejected for the reasons applied to the base claim, above.
Accordingly, claims 1-3, 8-12, 15, and 18-22 are rejected.
Claim Rejections - 35 USC § 112(a), Written Description/New Matter
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 1-3, 8-12, 15, and 18-22 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.
Brief Statement of the Issue(s)
Claim 1 was amended in the Reply filed 2/24/2026 to include new matter not supported by the originally filed disclosure commensurate in scope with the requirements of 35 USC 112(a).
The amended claims recite ill-described functional limitations reflecting outcomes Applicant hopes and wishes to achieve, but such functional limitations do not reflect any structure/function relationships, definitions, or exemplified embodiments of record.
Claim Scope
Claim 1 and 8 are representative of the pending claims scope and attempts to define a required dosage of ATIII by reference to an intended and hoped for result that the dosage is supposed to achieve (i.e., at amended claim 1, the dosage of ATIII must be “at levels sufficient to achieve an anti-FXa level of at least 0.2 IU/mL of plasma”, and at claim 8 the dosage of ATIII must be sufficient to increase “the patient’s ATIII plasma levels to about or greater than 1.3 IU/mL”).
Claim Interpretation
The applicable claim interpretations have been set forth above under 35 USC § 112(b) and in a separate claim interpretation section. Those discussions are incorporated herein.
Applicable Case Law
The MPEP states that "[w]hile there is no in haec verba requirment, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP 2163.
Regarding narrowing amendments attempting to carve a narrower genus from a broad and highly varied genus and laundry list disclosure, the case law and MPEP guidance states, per MPEP § 2163.05(II), that
The introduction of claim changes which involve narrowing the claims by introducing elements or limitations which are not supported by the as-filed disclosure is a violation of the written description requirement of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph. See, e.g., Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996) (a "laundry list" disclosure of every possible moiety does not constitute a written description of every species in a genus because it would not "reasonably lead" those skilled in the art to any particular species); In re Ruschig, 379 F.2d 990, 995, 154 USPQ 118, 123 (CCPA 1967) . . . . ; Rozbicki v. Chiang, 590 Fed.App’x 990, 996 (Fed. Cir. 2014) (non-precedential) (The court found that patentee, "while attempting to obtain the broadest claim language possible during prosecution, cannot now improperly narrow its language by importing limitations not supported by the claim language or written description."). In Ex parte Ohshiro, 14 USPQ2d 1750 (Bd. Pat. App. & Inter. 1989) . . . .
This courts have clearly stated that the mere disclosure of “each ... individual limitations” separately and distinctly, does not evidence possession of all combinations of all such limitations “as an integrated whole” because written description support requires more than the combination of “an amalgam of disclosures plucked selectively from the ... application” (see, e.g., Novozymes A/S v. DuPont Nutrition Biosciences APS, 723 F.3d 1336, 1349, 107 U.S.P.Q.2d 1457, 1467, 2013 BL 192990, 14 (Fed. Cir. 2013), explaining that the written description analysis requires “[t]aking each claim . . . as an integrated whole rather than as a collection of independent limitations”).
It is noted that reliance upon non-patent literature amounts to an improper incorporation by reference because a claim limitation is “essential material” and can only be incorporated by a proper reference to a U.S. patent or U.S. patent application publication (see, e.g., MPEP § 608.01(p); see also 37 C.F.R. 1.57(d)).
Lack of literal Support
The MPEP states that "[w]hile there is no in haec verba requirment, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP 2163. Therefore, it is pertinent to ascertain if literal support exists for the narrowed subgenus of amended claim 1.
Upon examination, claim 1 as presently recited fails to literally appear on record as an integrated whole. Notably, he mere disclosure of “each ... individual limitations” separately and distinctly, does not evidence possession of all combinations of all such limitations “as an integrated whole” because written description support requires more than the combination of “an amalgam of disclosures plucked selectively from the ... application” (see, e.g., Novozymes A/S v. DuPont Nutrition Biosciences APS, 723 F.3d 1336, 1349, 107 U.S.P.Q.2d 1457, 1467, 2013 BL 192990, 14 (Fed. Cir. 2013), explaining that the written description analysis requires “[t]aking each claim . . . as an integrated whole rather than as a collection of independent limitations”).
Actual Reduction to Practice
Zero examples of an in vivo method of treating blunt physical trauma patients by administering an anticoagulant in combination with ATIII were reduced to practice. The closest discloses of record pertain to ex vivo methods wherein a baseline of extant ATIII were monitored; however, such methods are excluded from the instant claim scope (see, e.g., Spec. filed 1/12/2021 at ¶¶[0068]-[0071], Figures 2 and 3A).
Assessment of whether disclosed species are representative of the claimed genus
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus (see, e.g., MPEP § 2163(II)(3)(a), MPEP §2163.03(V)). Here, the claim scope is potentially vast and highly varied because the claims read upon numerous combinations of numerous formulations of both anticoagulants and ATIII, each at different dosages and in different formulations.
Although the MPEP does not define what constitutes a sufficient number of representative species, the Courts have indicated that the disclosure of two species within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618. Therefore, the disclosure of zero species of the claimed invention cannot be said to provide sufficient disclosure to satisfy the written description requirement for the instantly claimed genus.
Lack of Implicit or Inherent Support
The MPEP states that "[w]hile there is no in haec verba requirment, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure." See MPEP 2163. As noted above, the claims are not literally supported by the originally filed disclosure. Accordingly, the relevant issue is whether or not the new amendments and resulting claim scope is implicitly or inherently supported by the originally filed disclosure.
Per MPEP § 2163(I)(B), “[a]n amendment to correct an obvious error does not constitute new matter where the ordinary artisan would not only recognize the existence of the error in the specification, but also recognize the appropriate correction. In re Oda, 443 F.2d 1200, 170 USPQ 268 (CCPA 1971)”. Here, no allegation that the amendments correct an obvious error has been made. Furthermore, upon inspection, Examiner is unable to identify any single “obvious error” that would lead to the instantly amended claim scope. Accordingly, the amendments cannot be said to correct an “obvious error”.
The originally filed disclosure provides no guidance for meaningfully interpreting the functional limitations at amended claims 1 and 8-12, which have been discussed in view of indefiniteness above (see, e.g., rejections under 35 USC § 112(b), above), and those discussions are incorporated into the instant rejection. As explained above under 35 USC 112(b), the prior art of record teaches that an ATIII baseline may refer to two different measurable things (see, e.g., discussion above regarding Moll et al.37 and Refaei38); that calculating a desired ATIII level based upon a measured baseline may be performed using multiple different formulas (see, e.g., discussion above regarding ThrombateInsert39, ATrynInsert40, and Liumbruno et al41 , incorporated herein); and that the functional limitations may be satisfied without administering any ATIII to a patient because natural ATIII levels may exceed “150%” (see, e.g., discussion above under 35 USC 112(b) regarding Dolan et al.42, ATrynInsert 43, Tahaineh et al.44, and ThrombateInsert45, incorporated herein). The originally filed disclosure provides zero guidance regarding the proper interpretation of the amended claim scope. Accordingly, such functional language merely reflects a desired and hoped for result that Applicant wishes to achieve, but fails to meaningfully inform artisans of how to actually achieve such outcomes. As explained above, it is unclear if the step of administering ATIII is actually optional (see, e.g., discussion above under 35 USC 112(b) regarding Dolan et al.46, ATrynInsert 47, Tahaineh et al.48, and ThrombateInsert49, incorporated herein).
In addition, it is noted that Kowal-Vern50 pertains to the treatment of a patient having a traumatic injury and reasonably informs artisans that a baseline of ATIII levels was determined, and that an amount of ATIII was administered with the intent to “maintain the ATIII plasma level at 175%” (see, e.g., Kowal at 98 at col I at final ¶), using the formula
Amount of ATIII to achieve desired level = [(desired ATIII level % - patient ATIII level % x (admission weight, kg)] divided by 1.4
(see, e.g., Kowal at 98 at col I-II at bridging ¶). However, Kowal discloses that the “dosages calculated to achieve a level of 175%” actually caused “the ATIII levels [to reach] 203%”(see, e.g., Kowal at 100 at col I at Section 4). This evidences that a targeted and “desired ATIII level %” and the level of ATIII actually achieved may differ by at least 28%. Accordingly, it is unclear how such known error recognized in the prior art may be accounted for in the instant claim, because it is simply not addressed. Accordingly, very close prior art exists51, and it is unclear if the level of “at 150%” may be incidentally achieved by administering ATIII to achieve a much lower “desired level”, such as 120%.
Claims 8-12 continue to recite functional limitations requiring the administration of an amount of ATIII sufficient to result in certain ATIII plasma levels (e.g., instant claim 8 requires administration of ATIII sufficient to “increase the patient’s ATIII plasma levels to about or greater than 1.3 IU/mL”, see similar limitations at claims 9-12)52. This is pertinent because it raises another basic, threshold question. Namely, “what concentrations of ATIII do or do not satisfy the claimed functional limitation?”. The original disclosure fails to address this very basic question. Upon review, the originally filed disclosure fails to address how much ATIII must be administered to a blunt physical trauma patient, in combination with an anticoagulant, to achieve an increase in the patient’s ATIII plasma levels to about or greater than 1.3 IU/mL (or other ranges at claims 8-12).
Accordingly, upon review, no inherent or implicit support for the instantly claimed invention exists as instantly claimed. The closest supporting disclosure pertains to unclaimed methods and methodologies, and laundry list disclosures that fail to meaningfully define the terms and limitations currently recited in the amended claims.
Predictability in the Art
Although the level of skill in the art is high, the predictability in the art is low due to the complexity of biological systems, biochemistry, patient populations, patient health, patient ATIII base levels, etc. Specifically, an artisan would not be able to predict or identify, a priori, and in the absence of any guidance, exactly what dosages of ATIII in combination with anticoagulants are included or excluded from the pending claim scope.
Examiner notes that, given the variability of ATIII levels upon treatment, the lack of structure/function relationships regarding functional limitations of record on record, and the extensive prior art53, to avoid infringement of the instantly amended claim scope, an artisan would be required to possess foreknowledge of information only obtainable after administration has already occurred.
Conclusion
Per MPEP § 2163, new or amended claims which introduce elements or limitations which are not supported by the as-filed disclosure violate the written description requirement (see, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971)). Here, the newly added claim limitations are not inherently, implicitly, or literally supported by the originally filed disclosure.
Examiner notes that if the instant Application were available as prior art, it would not be sufficient to support a rejection under 35 USC § 102 upon the instant claims. This is pertinent because although the original disclosure may render the newly amended claim scope obvious, obviousness is not the test for written description:
[A]n applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention" (see, e.g., Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398, emphasis added).
Therefore, although the originally-filed disclosure may render the instant claims obvious, “a description which renders obvious a claimed invention is not sufficient to satisfy the written description requirement of that invention” (see, Regents of the University of California v. Eli Lilly, 119 F.3d 1559, 1567 (Fed. Cir. 1997)) because “[o]ne shows that one is ‘in possession’ of the invention by describing the invention, with all its claimed limitations, not that which makes it obvious” (Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1571-72 (Fed. Cir. 1997) at 1572).
Per MPEP § 2163(I)(A), “the claimed invention as a whole may not be adequately described if the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional or known in the art”. Here, the amended claims recite and require functional limitations that are not unambiguously known in the prior art or otherwise unambiguously defined on record. Therefore, such lack of description fails to satisfy the written description requirement.
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). The courts have stated that “merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus” (see, e.g., AbbVie v. Janssen, 111 USPQ2d 1780 (Fed. Cir. 2014) at 1789). In addition, the Courts have stated
“[r]egardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004) (emphasis added).
This is pertinent because, in the instant case, Applicants have claimed a broad and highly varied genus comprising an unknown number of species defined by reference to one or more functional limitations; however, the originally filed disclosure has failed to identify any common structure/function relationship sufficient to permit an artisan to identify what exact ATIII dosages are included or excluded by the claim scope. This also means that it is prima facie unclear what prior art ATIII dosages infringe or do not infringe upon the pending claim scope.
In conclusion, for the reasons discussed above, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention.
Therefore, claims 1-3, 8-12, 15, and 18-22 are rejected.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 8-12, 15, and 18-22 are rejected under 35 U.S.C. 103 as being unpatentable over Sen54 and further in view of Refaei55 and Kowal-Vern56.
Claim interpretation: The applicable claim interpretation has been set forth above in preceding rejections and in a separate section, and those discussions are incorporated into the instant rejection. As explained in the Claim Interpretation section above, the amended dosage limitations at claim 1 are understood to be fully satisfied by dosages satisfying claims 8-12, which are understood to be fully satisfied by intravenously administering “about 42 IU/kg of body weight” of ATIII to any “blunt physical trauma patient” 57,58. Additional claim interpretations are set forth below.
Regarding instant claims 1-3, 8-12, 15, and 18, and the use of enoxaparin and ATIII to treat blunt physical trauma patients, Sen identifies that Enoxaparin and Antithrombin III were each administered to “blunt physical trauma” patients, namely patients with “Contusion-triggered” traumatic brain injuries (see, e.g., Sen at title, abs). Sen identifies that ATIII and enoxaparin both advantageously inhibit contusion-triggered cell death, inflammation, hemorrhage and apoptosis in patients after Severe traumatic brain injury (i.e., a type of blunt trauma) (see, e.g., Sen at title, abs). More specifically, Sen identifies that ATIII can be administered at 250 IU/kg via an intraperitoneal injection following head injury (see, e.g., Sen at 206 at col I at 1st partial ¶). Regarding instant claims 2-3, claims 2-3 do not require that the patients at issue actually suffer from VTE or venous thrombosis, but only that the treated patients be “at risk” of “the occurrence of” such things (see, e.g., MPEP § 2111.02(II)). Accordingly, instant claims 1-2 are understood to be fully satisfied by “contusion-triggered” TBIs as taught and evaluated by Sen. Regarding instant claims 1, 15, 18-22 and the administration of enoxaparin, Sen identifies that enoxaparin was administered at 0.5 mg/kg and 1 mg/kg (see, e.g., Sen at 206 at col I at 1st partial ¶). An artisan would readily appreciate that 0.5 to 1.0 mg/kg would correspond to a range of 35 mg to 70 mg for a 70 kg human adult. Per MPEP § 2144.05(I), where the claimed ranges “overlap or lie inside ranges disclosed by the prior art”, a prima facie case of obviousness exists; here the ranges at claims 18-22 overlap or lie inside the ranges disclosed in the prior art. In sum, an artisan would readily appreciate that both enoxaparin and ATIII could be advantageously administered to patients with TBIs in order to predictably, desirably, and advantageously inhibit contusion-triggered cell death, inflammation, hemorrhage and apoptosis in patients after severe traumatic brain injury (see, e.g., Sen at title, abs, 204 at col II).
The primary reference differs from the instant claims as follows: The primary reference does not explicitly teach or disclose the (i) step of administering of ATIII at the functionally defined amount recited at amended claims 1 and 8-12 (presumably satisfied by the administration of “about 42 IU/kg” of ATIII), (ii) intravenous administration of ATIII, (iii) the explicit combination of both ATIII and enoxaparin in a single patient population, or (iv) the step of “measuring a baseline” to determine an amount of ATIII to administer to a patient. However, such differences would be obvious.
Regarding the amounts of ATIII administered: Although Sen identifies that ATIII can be administered at 250 IU/kg (see, e.g., Sen at 206 at col I at 1st partial ¶), there is no evidence that such amounts of ATIII were optimal, and therefore an artisan would readily look to optimize the amount of ATIII utilized using standard intravenous administration to human patients. An artisan would review the prior art for typical ranges of ATIII commonly administered to human patients. For example, Refaei identifies that
From our review of the literature, the dose of AT used in the different studies ranges from 24 to 65 IU kg -1…
(see, e.g., Refaei at 7 at col I-II at bridging ¶).
Or otherwise
The dose of AT used in these studies ranged from 30 to 90 IU kg-1 daily….
(see, e.g., Refaei at 8 at col I at 1st full ¶).
Accordingly, an artisan would readily appreciate that humans could be safely treated with 24 to 90 IU/kg of ATIII. In combination with the teachings of Sen, an artisan attempting to optimize the amount of ATIII utilized to treat TBIs as suggested by Sen would readily minimize the amount utilized to advantageously lower treatment costs, and would evaluate amounts ranging from 24 IU/kg up to 250 IU/kg. As explained in the claim interpretation section, above, here the functional limitations recited at instant claims 1 and 8-12 are understood to be satisfied by the administration of “about 42 IU/kg” of ATIII; per MPEP § 2144.05(I), where the claimed ranges “overlap or lie inside ranges disclosed by the prior art”, a prima facie case of obviousness exists; here the ranges encompassed by the functional limitations at claims 1 and 8-12 are reasonably understood to overlap or lie inside the ranges disclosed in the prior art.
Regarding intravenous administration of ATIII, Refaei identifies that ATIII may be administered intravenously (see, e.g., Refaei at 3 at col I at 1st full ¶).
Regarding the step of “measuring a baseline” and administering ATIII in an amount sufficient to achieve a desired amount “at 150%” or more: Kowal-Vern pertains to the treatment of a patient having a traumatic injury and reasonably informs artisans that ATIII may be administered in amounts sufficient to “maintain the ATIII plasma level at 175%” (see, e.g., Kowal at 98 at col I at final ¶), but notes that the “dosages calculated to achieve a level of 175%” actually caused “the ATIII levels [to reach] 203%”(see, e.g., Kowal at 100 at col I at Section 4). Accordingly, calculated doses of ATIII were known in the art to not necessarily achieve the targeted plasma level of ATIII, but potentially yield higher levels. Kowal explains the basic formula for calculating a dosage of ATIII required to achieve a desired ATIII level, which is understood to be:
Amount of ATIII to achieve desired level = [(desired ATIII level % - patient ATIII level % x (admission weight, kg)] divided by 1.4
(see, e.g., Kowal at 98 at col I-II at bridging ¶). Kowal also provides a basic rationale explaining why doctors may target a “desired level” of ATIII above the normal range of 100%±20% (see, e.g., Kowal at Table 1 on 98); specifically, Kowal notes that any measured “baseline” reflects a dynamic level of ATIII in plasma, which is known to fluctuate in patients (see, e.g., Kowal at 100 at col I-II at §§ 4 and 5, noting that a targeted level of 175% resulted in the ATIII levels reaching “203% immediately after the last infusion and 145% at 4 h after the last infusion”, and explaining that “ATIII doses be high enough to raise the ATIII levels to 175% or higher to counteract and reduce the effects of the inflammatory mediators” but that this level may not be reachable due to fluid loss, hemodilution, and other issues). Accordingly, the “desired level” of ATIII would depend upon a physician assessment regarding how fast ATIII was being depleted between subsequent rounds of ATIII administration in an individual patient. Accordingly, Kowal identifies that
targeting a “desired level” of plasma ATIII above 150% was already known and routine in the prior art for trauma patients59;
the step of measuring a “baseline” value of ATIII in trauma patients, then calculating a required dosage of ATIII to administer to a trauma patient to achieve a “desired level” of ATIII based upon the measured baseline was already known and routine for trauma patients60;
the actual level of ATIII in plasma resulting from ATIII administration to achieve a desired level could result in ATIII levels that were over 25% over the “desired level”61, and therefore such treatments were known to have high error; and
Physicians were aware that ATIII levels could change with time, and that a dosage targeting a particular “desired level” would need to take into consideration how fast ATIII was being depleted62.
Accordingly, measuring a baseline to determine an amount of ATIII to administer to a trauma patient, and targeting levels at or above 175% were already known and practiced in the prior art.
Regarding the combination of both Enoxaparin and ATIII administration to treat trauma patients: ATIII administration had art-recognized benefits; Sen identifies that ATIII was an art-recognized “inhibitor of blood coagulation”, and had recognized “anti-inflammatory and anti-platelet effects” (see, e.g., Sen at 204 at col II at 1st full ¶). Sen identifies that enoxaparin had art-recognized benefits in traumatic brain injury patients; namely, enoxaparin was art-recognized as a low molecular weight heparin that was widely utilized for anticoagulation, and that was also reported to have neuroprotective effects in traumatic brain and spine injuries (see, e.g., Sen at 204 at col II at 1st full ¶). Accordingly, both compounds had art-recognized benefits and were taught for use in the treatment of trauma patients, including “blunt physical trauma” patients, namely patients with “Contusion-triggered” traumatic brain injuries (see, e.g., Sen at title, abs).
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): Per MPEP § 2144.06(I), "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Likewise, here the claimed invention is merely the combination of two “promising drugs in the treatment of traumatic brain injuries”, namely ATIII and Enoxaparin, wherein each would be simply administered and utilized consistent with the teachings and dosage ranges taught and disclosed in view of Sen, Refaei, and Kowal, wherein the combination would predictably and expectedly yield a treatment in TBI patients having neuroprotective and anti-inflammatory effects, exactly as taught and suggested by the primary reference (see, e.g., MPEP § 2144.06(I); see also MPEP § 2143(I)(A), (F)), and wherein an artisan would readily appreciate that ATIII could be administered to patients at amounts ranging from 24 IU/kg up to 250 IU/kg as taught by Refaei (see MPEP § 2144.05(I)) and wherein targeting a “desired level” of ATIII at or above 175% would be routine in trauma patients depending on a physician’s assessment of needs per the teachings of Kowal (see MPEP § 2144.05(I)).
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. The claimed invention appears to yield nothing more than what would have been expected and predicted by one of ordinary skill in the art, and no objective evidence to the contrary has been placed on record at this time.
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 administer known compounds at known ranges using known administration routes to a known patient population to achieve known and art-recognized results.
Accordingly, claims 1-3, 8-12, 15, and 18-22 are rejected.
Response to Arguments
Applicant's arguments filed 2/24/2026 have been fully considered, but have been rendered substantially moot in view of the new or revised claim rejection. Remaining applicable arguments are addressed below.
Rejections - 35 USC § 112(b)
It is the Examiner’s understanding that Applicant addresses the prior rejections under 35 USC §112(b) at pages 6-7 (see, e.g., Reply filed 2/24/2026 at 6 at final ¶ to 7 at 2nd full ¶).
The prior rejection(s) have been withdrawn and replaced with a new or revised rejection(s) that addresses the newly added claim limitations, which has rendered multiple arguments moot. Remaining applicable arguments are addressed below.
It is the Examiner’s understanding that Applicant alleges that because the expression “wherein the ATIII administration increases the patient’s ATIII plasma levels to about or greater than 1.2 IU/mL” has been deleted from claim 1, that the prior rejection of claims 1 and 8-12 exemplified in view of claim 1 has been overcome, although the same issue persists at unamended claims 8-12, which were included in the rejection of record (see, e.g., Reply filed 2/24/2026 at 6 at final ¶; see Action mailed 8/27/2025 at 9-10). This is not persuasive because the rejection applied to all analogous functional limitations at claims 8-12, which have not been amended. Accordingly, the same issue remains rendering the claim scope indefinite.
It is the Examiner’s understanding that Applicant alleges that amended claim 1 “provides an objective and quantifiable dosing parameter” (see, e.g., Reply filed 2/24/2026 at 7 at 1st full ¶). This is incorrect as explained in the new and revised rejections necessitated by Applicant’s amendments. The claim scope continues to require foreknowledge of results only ascertainable after completion of the claimed steps and when multiple assumptions are made regarding formulas utilized and ATIII function measured, etc., which means that the claim is not defined in a manner that permits an artisan to actually avoid infringement, which is the primary purpose of the requirement as explained at MPEP §2173.
Accordingly, all applicable arguments pertaining to 35 USC 112(b) have been fully considered but not found persuasive. All new and revised rejections were necessitated by Applicant’s amendments.
Rejections - 35 USC § 112(a)
It is the Examiner’s understanding that Applicant addresses the prior rejections under 35 USC §112(a) at pages 7-10 (see, e.g., Reply filed 2/24/2026 at 7 at penultimate ¶ to 10 at 1st full ¶). The prior rejection has been withdrawn and replaced with a new rejection that addresses the newly added claim limitations, which has rendered multiple arguments moot. Remaining applicable arguments are addressed below.
It is the Examiner’s understanding that Applicant alleges that because the expression “wherein the ATIII administration increases the patient’s ATIII plasma levels to about or greater than 1.2 IU/mL” has been deleted from claim 1, that the prior rejection of claims 1 and 8-12 exemplified in view of claim 1 has been overcome, although the same issue continues to persist at unamended claims 8-12 (see, e.g., Reply filed 2/24/2026 at 8 at 2nd to 3rd full ¶¶). This is not persuasive because although the functional language was replaced at claim 1, analogous functional limitations remain at unamended claims 8-12, and therefore the issue with the claim scope has not been fully addressed.
It is the Examiner’s understanding that Applicant admits that no examples of the claimed invention, as actually claimed, were reduced to practice, but alleges that the written description requirement does not require in vivo working examples (see, e.g., Reply filed 2/24/2026 at 8-9 at bridging ¶, 9 at 1st full to 2nd full ¶). Examiner notes that reduction to practice is one factor considered in a Written Description analysis per MPEP § 2163, but is not the only factor relied upon by the Examiner to support the rejection. Here, Applicant refers to unclaimed ex vivo methods that lack the steps and functional limitations presently required by the pending claims (see, e.g., Reply filed 2/24/2026 at 9 at 1st full to 2nd full ¶). While this disclosure regarding ex vivo assays has been fully considered and evidences possession of an ex vivo plasma assay, it does not provide evidence of possession of the instantly claimed method because such ex vivo assays do not explain or address administration to blunt physical trauma patients, via intravenous administration, a functionally determined amount of ATIII “at 150% of more” of “the measured baseline level and sufficient to achieve an anti-FXa level of at least 0.2 IU/mL of plasma” as well as an anticoagulant (i.e., enoxaparin), wherein the step of “measuring a baseline level of antithrombin III (ATIII) in the patient” is also performed, as required by the instantly claimed invention. As noted in the rejection, zero examples of such methods were disclosed on record, and therefore examples of an unclaimed ex vivo assay lacking the limitations of the claimed invention are insufficient to establish possession of a completely different invention having different limitations.
As noted above in the revised rejection, the amendments amount to an introduction of new matter that is not literally, inherently, or implicitly supported by the originally filed disclosure. Applicant provides zero guidance to where the genus of inventions encompassed by newly amended claim 1 are actually literally, inherently, or implicitly disclosed with all limitations as presently claimed set forth as an integrated whole (see, e.g., Novozymes A/S v. DuPont Nutrition Biosciences APS, 723 F.3d 1336, 1349, 107 U.S.P.Q.2d 1457, 1467, 2013 BL 192990, 14 (Fed. Cir. 2013), explaining that the written description analysis requires “[t]aking each claim . . . as an integrated whole rather than as a collection of independent limitations”).
Accordingly, all applicable arguments pertaining to 35 USC 112(a) have been fully considered but not found persuasive. All new and revised rejections were necessitated by Applicant’s amendments.
Rejections - 35 USC § 103(a)
It is the Examiner’s understanding that Applicant addresses the prior rejections under 35 USC §112(a) at pages 10-12 (see, e.g., Reply filed 2/24/2026 at 10 at 2nd full ¶ to 12 at 1st partial ¶). The prior rejection has been withdrawn and replaced with a new rejection that addresses the newly added claim limitations, which has rendered multiple arguments moot. Remaining applicable arguments are addressed below.
It is the Examiner’s understanding that Applicant alleges that the withdrawn rejection does not address a step of measuring a baseline and administering ATII sufficient to achieve that baseline (see, e.g., Reply filed 2/24/2026 at 10 at 2nd full ¶ to 11 at 1st full ¶). The revised rejection explicitly addresses the state of the art regarding ATIII administration in view of a third reference.
It is the Examiner’s understanding that Applicant alleges that Sen and Refaei “do not teach or suggest the claimed combination or dosing” (see, e.g., Reply filed 2/24/2026 at 11 at 2nd full ¶). This difference is noted in the difference statement and is explicitly addressed in the obviousness statement utilizing a rationale supported by MPEP § 2144.06(I) and MPEP § 2143(I)(A) and (F). Applicant fails to acknowledge or address these rationales, or identify any element of such rationales not supported by the facts of record. Accordingly, such arguments are not persuasive.
It is the Examiner’s understanding that Applicant alleges that an artisan would not administer ATIII in an amount of 150% or more, presumably on the basis that the prior art “teaches away” from this amount because 80-120% is typically viewed as “normal” (see, e.g., Reply filed 2/24/2026 at 11-12 at bridging ¶). Examiner notes that this argument is not persuasive because none of prior art references at issue “teach away” from the claimed invention since they do not actually “criticize, discredit, or otherwise discourage the solution claimed” (see, e.g., MPEP § 2141.02(VI)). Furthermore, Applicant has not identified any disclosure that “criticizes, discredits, or otherwise discourages the solution claimed”. Rather, the art of record clearly evidences that a wide range of ATIII dosages may be administered to patients, and that physicians have previously administered trauma patients ATIII sufficient to achieve a target level of 175% (see, e.g., Kowal at 98 at col I at final ¶, 100 at col I at Section 4). Accordingly, no “teaching away” has been identified on record, and therefore such arguments are not persuasive.
It is the Examiner’s understanding that Applicant’s statements amount to a suggestion that the Examiner’s position would be met with skepticism of experts (see, e.g., Reply filed 2/24/2026 at 11-12 at bridging ¶, stating what one of ordinary skill in the art would not consider). If Applicant means to suggest the existence of skepticism of experts, such evidence should be filed per MPEP § 716.05 as evidence is required to establish skepticism of experts. In the absence of such evidence, such statements are understood to be unsupported conjecture of counsel. 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)), including “all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments” (see, e.g., MPEP § 2123(I)), and no objective evidence rebutting this presumption has been placed on record to date.
Zero evidence of unexpected results commensurate in scope with the requirements of MPEP § 716.02 have been placed on record to date. Rather, the administration of known compounds to a known patient population within known dosage ranges would be predicted and expected to yield only the benefits and functionality taught and disclosed by the prior art.
All arguments raised by the Applicant(s) have been fully considered but not found persuasive for the reasons set forth above, or are otherwise moot at this time.
Accordingly, no claims are allowed.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. This list is not exhaustive and Examiner notes that the prior art in this particular field is extensive.
Yamaguchi et al. (Successful treatment of a massive pulmonary embolism using rivaroxaban in a patient with antithrombin III deficiency. J Cardiol Cases, vol. 16(5):144-147 ( 2017 Jul 26); cited in previous action) identifies that circa 2017, it was routine to administer exogenous AT-III and heparin to patients with AT-III deficiency (see, e.g., id. at 145 at col II).
Avidan et al. (Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass, J Thorac Cardiovasc Surg., vol. 130(1):107-13 (2005 Jul); cited in previous action) discloses a study wherein patients received heparin and ATIII in perioperative patients (see, e.g., id. at abs).
Spiess (Treating heparin resistance with antithrombin or fresh frozen plasma, Ann Thorac Surg., vol. 85(6):2153-60 (2008 Jun); cited in previous action) identifies that heparin resistance is routinely treated with AT concentrate or AT-containing plasma, circa 2008 (see, e.g., id. at 2154 col II, passim).
US 4,689,323 (Aug. 25, 1987; cited in previous action) teaches and discloses “a method for preventing and treating thromboembolisms by administering to a human patient a therapeutically effective amount of the complex or preparation”, wherein the preparation is a heparin-antithrombin III complex (see, e.g., US’323 at abs, col I at lines 5-45, col 4 at lines 25-38, claims 4, 16, 18, 20, 22, and 24). The prior art teaches that the heparin used may be low molecular weight heparin (see, e.g., US’323 at col 9 at lines 64 to col 10 at line 21).
Avidan63 discloses a method of administering heparin and recombinant human antithrombin (ATIII) to “heparin-resistant patients scheduled to undergo cardiac surgery necessitating cardiopulmonary bypass” (see, e.g., Avidan at title, abs, Fig. 1 on 278). Such patients are “at risk” because they are perioperative patients “scheduled to undergo cardiac surgery necessitating cardiopulmonary bypass” (see, e.g., Avidan at title, abs, Fig. 1 on 278). Avidan teaches and discloses a method of administering 400 U/Kg of Heparin (300 U/kg followed by 100 U/Kg), followed by administration of 75 U/kg of recombinant human antithrombin [rhAT] (see, e.g., Avidan at Fig. 1 on 278, Table 2 on 280).
Moll et al.64 asks “How are Antithrombin Levels measured?” (see, e.g., Moll at 1 at § “How are Antithrombin levels Measured” to p. 2 at 1st partial ¶), and explains that
…Two different antithrombin tests can be done, (a) an antithrombin antigen level and (b) an antithrombin activity level (also called “functional test”). The antithrombin antigen test determines how much of the protein is present in the blood. The antithrombin activity test determines whether the antithrombin that is present actually works. . . .
Activity and antigen levels are typically expressed in “percent.” Normal ranges differ from lab to lab, but typically are approximately 80% – 120 %.
Accordingly, both the “antithrombin antigen level” test and the “antithrombin activity level” test are used in the art, and are “typically expressed in ‘percent’” (see id), but actually measure different aspects (i.e., ATIII protein levels overall, or functional ATIII protein). Accordingly, it is unclear if “150%” refers to measurable “antithrombin antigen level” or the measurable “antithrombin activity level”. Accordingly, the prior art of NATT addresses that antithrombin levels vary substantially:
Activity and antigen levels are typically expressed in “percent.” Normal ranges differ from lab to lab, but typically are approximately 80% – 120 %.
(see, e.g., Moll at 1 at § “How are Antithrombin levels Measured” to p. 2 at 1st partial ¶).
ThrombateInsert65 and ATrynInsert66 establish that a single, accepted “normal range” for ATIII does not exist. Accordingly, the dosage of ATIII required to achieve a particular desired result is reasonably understood to substantially vary depending upon the type of ATIII administered (e.g., blood product vs. recombinant) (see, e.g., ThrombateInsert at 4 at § Dosage; see also ATrynInsert at 1 at § Dosage). In addition, the dosage of administered ATIII required to achieve a particular desired result depends upon patient status (see, e.g., ATrynInsert at 1 at § Dosage, noting that patients weight and surgical or pregnancy status impacts dosage). In fact, it is well understood in the prior art that ATIII dosage is “individualized for each patient” (see, e.g., ATrynInsert at 1 at § Dosage), and “should be determined on an individual basis” (see, e.g., ThrombateInsert at 4 at § Dosage). This is pertinent because ThrombateInsert discloses that the amount of ATIII administered should be determined using the formula
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70
415
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(see, e.g., ThrombateInsert at 4 at § Dosage). However, ATrynInsert informs artisans that the amount of ATIII administered should be determined using the formulas
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218
674
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(see, e.g., ATrynInsert at 1 at § Dosage).
Dolan67 identifies that, depending upon age and sex, ATIII levels may naturally range from 0.72-1.69 IU/mL in plasma (see, e.g., Dolan at abs). Presumably this natural range corresponds to “72%” up to “169%”68.
Kowal-Vern69 identifies and teaches that Antithrombin III was administered to “maintain the ATIII plasma level at 175%” (see, e.g., Kowal at 98 at col I at final ¶), but identifies that the “dosages calculated to achieve a level of 175%” actually caused “the ATIII levels [to reach] 203%”(see, e.g., Kowal at 100 at col I at Section 4).
Tahaineh et al.70identifies that enoxaparin alone is capable achieving “an anti-FXa level of at least 0.2 IU/ml in plasma”, at some concentrations and in some patients as taught by the prior art:
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504
787
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(see, e.g., Tahaineh et al. at abs, 68 at Fig. 2). Notably, the effect of enoxaparin on Anti-Xa levels is also gender-dependent (see, e.g., Tahaineh at Fig. 3 on 68).
Walker71 pertains to the dosing of Enoxaparin in general trauma patients (see, e.g., Walker at title, abs).
Stockton72 discloses that Antithrombin III was commonly administered at a dosage of 29-79 units/kg (see, e.g., Stockton at Table 2 on 20).
Meister73 is pertinent to the instant invention, and the teachings of the reference were previously set forth on record (see, e.g., Action mailed 7/21/2023 at 20-29), and those discussions are incorporated herein.
Ting74 is pertinent to the instant invention, and the teachings of the reference were previously set forth on record (see, e.g., Action mailed 7/21/2023 at 20-29), and those discussions are incorporated herein.
Tourneau75 is pertinent to the instant invention, and the teachings of the reference were previously set forth on record (see, e.g., Action mailed 7/21/2023 at 20-29), and those discussions are incorporated herein.
Tahaineh76 is pertinent to the instant invention, and the teachings of the reference were previously set forth on record (see, e.g., Action mailed 7/21/2023 at 20-29), and those discussions are incorporated herein.
Konkle77 is pertinent to the instant invention, and the teachings of the reference were previously set forth on record (see, e.g., Action mailed 7/21/2023 at 30-39), and those discussions are incorporated herein.
Gill78 is pertinent to the instant invention, and the teachings of the reference were previously set forth on record (see, e.g., Action mailed 7/21/2023 at 35-39), and those discussions are incorporated herein.
Luciano79 is pertinent to the instant invention, and the teachings of the reference were previously set forth on record (see, e.g., Action mailed 7/21/2023 at 35-39), and those discussions are incorporated herein.
LucianoII80 is pertinent to the instant invention, and the teachings of the reference were previously set forth on record (see, e.g., Action mailed 7/21/2023 at 35-39), and those discussions are incorporated herein.
Conclusion
No claims are allowed.
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 RANDALL L BEANE whose telephone number is (571)270-3457. The examiner can normally be reached Mon.-Fri., 7 AM to 2 PM ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko G. Garyu can be reached at (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/RANDALL L BEANE/Primary Examiner, Art Unit 1654
1 See, e.g., Action mailed 1/24/2025 at 2-3.
2 See, e.g., Action mailed 1/24/2025 at 2-3.
3 “About” is ±20%, and therefore this range is understood to be 16 mg to 216 mg.
4 “About” is ±20%, and therefore this range is understood to be 0.08 to to 3 mg/kg.
5 See action mailed 7/21/2023 at 5-6, 10-19.
6 See action mailed 7/21/2023 at 5-6, 10-19.
7 “About” is ±20%, and therefore “about 42 IU/kg” is understood to be 33.6 to 50.4 IU/kg of body weight.
8 See 37 CFR 1.56(b)(1)-(3); see also Teva Pharmaceuticals USA, Inc. v. Sandoz, Inc., 789 F. 3d 1335 (2015), at 1343, stating “We have said before, and reaffirm today, that past and future prosecution of related patents may be relevant to the construction of a given claim term”. See, also, Springs Window Fashions LP v. Novo Indus., L.P., 323 F.3d 989, 995 (Fed.Cir.2003), noting that “The public notice function of a patent and its prosecution history requires that a patentee be held to what he declares during the prosecution of his patent”.
9 See, e.g., Dolan et al., Protein C, antithrombin III and plasminogen: effect of age, sex and blood group. Br J Haematol. 1994 Apr;86(4):798-803. doi: 10.1111/j.1365-2141.1994.tb04832.x. PMID: 7918075; hereafter “Dolan”; cited in previous action.
10 see, e.g., ATrynInsert at 1 at § Dosage, noting that “1.50” and “1.69 IU/mL” would correspond approximately to an activity level of 150% or 169% in some patients because ATryn identifies that “between 80%-120%” corresponds to “0.8-1.2 IU/mL” in some “normal” patients.
11 Sen et al., Antithrombin III and enoxaparin treatment inhibit contusion-triggered cell death, inflammation, hemorrhage and apoptosis after severe traumatic brain injury in rats. Turk Neurosurg. 2011;21(2):203-9. doi: 10.5137/1019-5149.JTN.3646-10.1. PMID: 21534203; cited in previous action.
12 Refaei et al., Management of Venous Thromboembolism in Patients with Hereditary Antithrombin Deficiency and Pregnancy: Case Report and Review of the Literature. Case Rep Hematol. 2017;2017:9261351. doi: 10.1155/2017/9261351. Epub 2017 Jan 10. PMID: 28168066; PMCID: PMC5259678; hereafter “Refaei”; cited in previous action.
13 See also prior rejection in Action mailed 5/29/2025 at 14-18, which included calculations showing differences in administered amounts of ATIII depending upon formula relied upon.
14 See, e.g., Kowal-Vern et al., Antithrombin III concentrate in the acute phase of thermal injury. Burns. 2000 Feb;26(1):97-101. doi: 10.1016/s0305-4179(99)00099-6. PMID: 10630326; hereafter “Kowal”; cited in previous action.
15 See, e.g., Action mailed 11/15/2022 at 11-17, discussing anticipatory art; see also Action mailed 7/21/2023 at 20-26, discussing anticipatory art; see also Action mailed 5/29/2024 at 32-39, discussing anticipatory art; see also Action mailed 1/24/2025 at 16-19, discussing obviousness in view of prior art; see also, below under 35 USC §§ 102 or 103).
16 See, e.g., Antithrombin III (Human), Thrombate III®, Product Insert 08941279 (Rev. April 2012), Talecris Biotherapeutics, 7 pages; hereafter “ThrombateInsert”; cited in previous action.
17 See, e.g., ATryn, Antithrombin (Recombinant) Package Insert (Feb. 3, 2009), GTC Biotherapeutics, Inc.; hereafter “ATrynInsert”, cited in previous action.
18 Liumbruno et al., Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) Working Party. Recommendations for the use of antithrombin concentrates and prothrombin complex concentrates. Blood Transfus. 2009 Oct;7(4):325-34. doi: 10.2450/2009.0116-09. PMID: 20011645; PMCID: PMC2782811.
19 See, e.g., Action mailed 11/15/2022 at 11-17, discussing anticipatory art; see also Action mailed 7/21/2023 at 20-26, discussing anticipatory art; see also Action mailed 5/29/2024 at 32-39, discussing anticipatory art; see also Action mailed 1/24/2025 at 16-19, discussing obviousness in view of prior art; see also, below under 35 USC §§ 102 or 103).
20 See also Liumbruno et al. at 327 at col I at § “Calculation”, explaining that “the administration of 1 UI/kg of body weight increases plasma AT activity by 1.5%”, which suggests administration of 100 UI/kg would achieve 150% or more in any patient, with a reasonable expectation of success.
21 Moll et al., Antithrombin Deficiency: An In-Depth Guide for Patients and Health Care Providers, National Alliance for Thrombosis & Thrombophilia, 16 pages (May 1, 2009); hereafter “NATT”; cited in previous action.
22 Refaei et al., Management of Venous Thromboembolism in Patients with Hereditary Antithrombin Deficiency and Pregnancy: Case Report and Review of the Literature. Case Rep Hematol. 2017;2017:9261351. doi: 10.1155/2017/9261351. Epub 2017 Jan 10. PMID: 28168066; PMCID: PMC5259678; hereafter “Refaei”; cited in previous action.
23 See, e.g., Action mailed 11/15/2022 at 11-17, discussing anticipatory art; see also Action mailed 7/21/2023 at 20-26, discussing anticipatory art; see also Action mailed 5/29/2024 at 32-39, discussing anticipatory art; see also Action mailed 1/24/2025 at 16-19, discussing obviousness in view of prior art; see also, below under 35 USC §§ 102 or 103).
24 See also Liumbruno et al. at 327 at col I at § “Calculation”, explaining that “the administration of 1 UI/kg of body weight increases plasma AT activity by 1.5%”, which suggests administration of 100 UI/kg would achieve 150% or more in any patient, with a reasonable expectation of success.
25 See, e.g., Dolan et al., Protein C, antithrombin III and plasminogen: effect of age, sex and blood group. Br J Haematol. 1994 Apr;86(4):798-803. doi: 10.1111/j.1365-2141.1994.tb04832.x. PMID: 7918075; hereafter “Dolan”; cited in previous action.
26 see, e.g., ATrynInsert at 1 at § Dosage, noting that “1.50” and “1.69 IU/mL” would correspond approximately to an activity level of 150% or 169% in some patients because ATryn identifies that “between 80%-120%” corresponds to “0.8-1.2 IU/mL” in some “normal” patients.
27 Tahaineh et al., Anti-factor Xa levels in obese patients receiving enoxaparin for treatment and prophylaxis indications. Clin Pharmacol. 2018 May 18;10:63-70. doi: 10.2147/CPAA.S161599. PMID: 29849468; PMCID: PMC5965377; hereafter “Tahaineh”; cited in previous action.
28 See, e.g., Antithrombin III (Human), Thrombate III®, Product Insert 08941279 (Rev. April 2012), Talecris Biotherapeutics, 7 pages; hereafter “ThrombateInsert”; cited in previous action.
29 See, e.g., Action mailed 11/15/2022 at 11-17, discussing anticipatory art; see also Action mailed 7/21/2023 at 20-26, discussing anticipatory art; see also Action mailed 5/29/2024 at 32-39, discussing anticipatory art; see also Action mailed 1/24/2025 at 16-19, discussing obviousness in view of prior art; see also, below under 35 USC §§ 102 or 103).
30 See also Liumbruno et al. at 327 at col I at § “Calculation”, explaining that “the administration of 1 UI/kg of body weight increases plasma AT activity by 1.5%”, which suggests administration of 100 UI/kg would achieve 150% or more in any patient, with a reasonable expectation of success.
31 See, e.g., Dolan et al., Protein C, antithrombin III and plasminogen: effect of age, sex and blood group. Br J Haematol. 1994 Apr;86(4):798-803. doi: 10.1111/j.1365-2141.1994.tb04832.x. PMID: 7918075; hereafter “Dolan”; cited in previous action.
32 see, e.g., ATrynInsert at 1 at § Dosage, noting that “1.50” and “1.69 IU/mL” would correspond approximately to an activity level of 150% or 169% in some patients because ATryn identifies that “between 80%-120%” corresponds to “0.8-1.2 IU/mL” in some “normal” patients.
33 See, e.g., Action mailed 11/15/2022 at 11-17, discussing anticipatory art; see also Action mailed 7/21/2023 at 20-26, discussing anticipatory art; see also Action mailed 5/29/2024 at 32-39, discussing anticipatory art; see also Action mailed 1/24/2025 at 16-19, discussing obviousness in view of prior art; see also, below under 35 USC §§ 102 or 103).
34 See, e.g., Dolan et al., Protein C, antithrombin III and plasminogen: effect of age, sex and blood group. Br J Haematol. 1994 Apr;86(4):798-803. doi: 10.1111/j.1365-2141.1994.tb04832.x. PMID: 7918075; hereafter “Dolan”; cited in previous action.
35 see, e.g., ATrynInsert at 1 at § Dosage, noting that “1.50” and “1.69 IU/mL” would correspond approximately to an activity level of 150% or 169% in some patients because ATryn identifies that “between 80%-120%” corresponds to “0.8-1.2 IU/mL” in some “normal” patients.
36 See, e.g., MPEP § 2173, explaining that the purpose of 35 USC § 112(b) is to “ensure that the scope of the claims is clear so the public is informed of the boundaries of what constitutes infringement of the patent”.
37 Moll et al., Antithrombin Deficiency: An In-Depth Guide for Patients and Health Care Providers, National Alliance for Thrombosis & Thrombophilia, 16 pages (May 1, 2009); hereafter “NATT”; cited in previous action; at 1 at § “How are Antithrombin levels Measured” to p. 2 at 1st partial ¶.
38 Refaei et al., Management of Venous Thromboembolism in Patients with Hereditary Antithrombin Deficiency and Pregnancy: Case Report and Review of the Literature. Case Rep Hematol. 2017;2017:9261351. doi: 10.1155/2017/9261351. Epub 2017 Jan 10. PMID: 28168066; PMCID: PMC5259678; hereafter “Refaei”; cited in previous action; at 2 at col II at § 2, explaining that the reference range for immunological AT level is 0.80-1.20 U/mL, but that the reference range for functional AT levels is 0.77-1.25 U/mL.
39 See, e.g., Antithrombin III (Human), Thrombate III®, Product Insert 08941279 (Rev. April 2012), Talecris Biotherapeutics, 7 pages; hereafter “ThrombateInsert”; cited in previous action; at 4 at § Dosage.
40 See, e.g., ATryn, Antithrombin (Recombinant) Package Insert (Feb. 3, 2009), GTC Biotherapeutics, Inc.; hereafter “ATrynInsert”, cited in previous action; at 1 at § Dosage, wherein “100” is understood to be a desired level of ATIII.
41 Liumbruno et al., Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) Working Party. Recommendations for the use of antithrombin concentrates and prothrombin complex concentrates. Blood Transfus. 2009 Oct;7(4):325-34. doi: 10.2450/2009.0116-09. PMID: 20011645; PMCID: PMC2782811; at 327 at col I at § Calculation of the dose of AT to administer.
42 See, e.g., Dolan et al., Protein C, antithrombin III and plasminogen: effect of age, sex and blood group. Br J Haematol. 1994 Apr;86(4):798-803. doi: 10.1111/j.1365-2141.1994.tb04832.x. PMID: 7918075; hereafter “Dolan”; cited in previous action; at abs; i.e., the natural range of ATIII varies from “72%” up to “169%”
43 see, e.g., ATrynInsert at 1 at § Dosage, noting that “1.50” and “1.69 IU/mL” would correspond approximately to an activity level of 150% or 169% in some patients because ATryn identifies that “between 80%-120%” corresponds to “0.8-1.2 IU/mL” in some “normal” patients.
44 Tahaineh et al., Anti-factor Xa levels in obese patients receiving enoxaparin for treatment and prophylaxis indications. Clin Pharmacol. 2018 May 18;10:63-70. doi: 10.2147/CPAA.S161599. PMID: 29849468; PMCID: PMC5965377; hereafter “Tahaineh”; cited in previous action; at abs, 68 at Fig. 2
45 See, e.g., ThrombateInsert at 4 at § Dosage .
46 See, e.g., Dolan et al., Protein C, antithrombin III and plasminogen: effect of age, sex and blood group. Br J Haematol. 1994 Apr;86(4):798-803. doi: 10.1111/j.1365-2141.1994.tb04832.x. PMID: 7918075; hereafter “Dolan”; cited in previous action; at abs; i.e., the natural range of ATIII varies from “72%” up to “169%”
47 see, e.g., ATrynInsert at 1 at § Dosage, noting that “1.50” and “1.69 IU/mL” would correspond approximately to an activity level of 150% or 169% in some patients because ATryn identifies that “between 80%-120%” corresponds to “0.8-1.2 IU/mL” in some “normal” patients.
48 Tahaineh et al., Anti-factor Xa levels in obese patients receiving enoxaparin for treatment and prophylaxis indications. Clin Pharmacol. 2018 May 18;10:63-70. doi: 10.2147/CPAA.S161599. PMID: 29849468; PMCID: PMC5965377; hereafter “Tahaineh”; cited in previous action; at abs, 68 at Fig. 2
49 See, e.g., ThrombateInsert at 4 at § Dosage .
50 See, e.g., Kowal-Vern et al., Antithrombin III concentrate in the acute phase of thermal injury. Burns. 2000 Feb;26(1):97-101. doi: 10.1016/s0305-4179(99)00099-6. PMID: 10630326; hereafter “Kowal”; cited in previous action.
51 See, e.g., Action mailed 11/15/2022 at 11-17, discussing anticipatory art; see also Action mailed 7/21/2023 at 20-26, discussing anticipatory art; see also Action mailed 5/29/2024 at 32-39, discussing anticipatory art; see also Action mailed 1/24/2025 at 16-19, discussing obviousness in view of prior art; see also, below under 35 USC §§ 102 or 103).
52 “About” is interpreted as set forth in the claim interpretation section, and means ±20% of a value. So “about” 1.3 would include 1.04 IU/mL.
53 See, e.g., Action mailed 11/15/2022 at 11-17, discussing anticipatory art; see also Action mailed 7/21/2023 at 20-26, discussing anticipatory art; see also Action mailed 5/29/2024 at 32-39, discussing anticipatory art; see also Action mailed 1/24/2025 at 16-19, discussing obviousness in view of prior art; see also, below under 35 USC §§ 102 or 103.
54 Sen et al., Antithrombin III and enoxaparin treatment inhibit contusion-triggered cell death, inflammation, hemorrhage and apoptosis after severe traumatic brain injury in rats. Turk Neurosurg. 2011;21(2):203-9. doi: 10.5137/1019-5149.JTN.3646-10.1. PMID: 21534203; cited in previous action.
55 Refaei et al., Management of Venous Thromboembolism in Patients with Hereditary Antithrombin Deficiency and Pregnancy: Case Report and Review of the Literature. Case Rep Hematol. 2017;2017:9261351. doi: 10.1155/2017/9261351. Epub 2017 Jan 10. PMID: 28168066; PMCID: PMC5259678; hereafter “Refaei”; cited in previous action.
56 See, e.g., Kowal-Vern et al., Antithrombin III concentrate in the acute phase of thermal injury. Burns. 2000 Feb;26(1):97-101. doi: 10.1016/s0305-4179(99)00099-6. PMID: 10630326; hereafter “Kowal”; cited in previous action.
57 See 37 CFR 1.56(b)(1)-(3); see also Teva Pharmaceuticals USA, Inc. v. Sandoz, Inc., 789 F. 3d 1335 (2015), at 1343, stating “We have said before, and reaffirm today, that past and future prosecution of related patents may be relevant to the construction of a given claim term”. See, also, Springs Window Fashions LP v. Novo Indus., L.P., 323 F.3d 989, 995 (Fed.Cir.2003), noting that “The public notice function of a patent and its prosecution history requires that a patentee be held to what he declares during the prosecution of his patent”.
58 See, e.g., Reply filed 11/26/2024 at 5-6, and claims 1 and 6-13 as filed 11/26/2024; see Action mailed 1/24/2025 at 7-8.
59 See, e.g., Kowal at 98 at col I-II at bridging ¶, 100 at col I at Section 4.
60 See, e.g., Kowal at 98 at col I-II at bridging ¶, 100 at col I at Section 4.
61 See, e.g., Kowal at 98 at col I-II at bridging ¶, 100 at col I at Section 4.
62 See, e.g., Kowal at 100 at col I-II at §§ 4 and 5.
63 Avidan et al. (Phase III, Double-blind, Placebo-controlled, Multicenter Study on the Efficacy of Recombinant Human Antithrombin in Heparin-resistant Patients Scheduled to Undergo Cardiac Surgery Necessitating Cardiopulmonary Bypass, Anesthesiology, vol. 102:276-284 (2005); hereafter “Avidan”; cited in previous action)
64 Moll et al., Antithrombin Deficiency: An In-Depth Guide for Patients and Health Care Providers, National Alliance for Thrombosis & Thrombophilia, 16 pages (May 1, 2009); hereafter “NATT”; cited in previous action.
65 See, e.g., Antithrombin III (Human), Thrombate III®, Product Insert 08941279 (Rev. April 2012), Talecris Biotherapeutics, 7 pages; hereafter “ThrombateInsert”; cited in previous action.
66 See, e.g., ATryn, Antithrombin (Recombinant) Package Insert (Feb. 3, 2009), GTC Biotherapeutics, Inc.; hereafter “ATrynInsert”, cited in previous action.
67 See, e.g., Dolan et al., Protein C, antithrombin III and plasminogen: effect of age, sex and blood group. Br J Haematol. 1994 Apr;86(4):798-803. doi: 10.1111/j.1365-2141.1994.tb04832.x. PMID: 7918075; hereafter “Dolan”; cited in previous action.
68 see, e.g., ATrynInsert at 1 at § Dosage, noting that “1.50” and “1.69 IU/mL” would correspond approximately to an activity level of 150% or 169% in some patients because ATryn identifies that “between 80%-120%” corresponds to “0.8-1.2 IU/mL” in some “normal” patients.
69 See, e.g., Kowal-Vern et al., Antithrombin III concentrate in the acute phase of thermal injury. Burns. 2000 Feb;26(1):97-101. doi: 10.1016/s0305-4179(99)00099-6. PMID: 10630326; hereafter “Kowal”; cited in previous action.
70 Tahaineh et al., Anti-factor Xa levels in obese patients receiving enoxaparin for treatment and prophylaxis indications. Clin Pharmacol. 2018 May 18;10:63-70. doi: 10.2147/CPAA.S161599. PMID: 29849468; PMCID: PMC5965377; hereafter “Tahaineh”; cited in previous action.
71 Walker et al., Increased Enoxaparin Dosing for Venous Thromboembolism Prophylaxis in General Trauma Patients. Ann Pharmacother. 2017 Apr;51(4):323-331. doi: 10.1177/1060028016683970. Epub 2016 Dec 15. PMID: 28228055; cited in previous action.
72 Stockton et al., Antithrombin III Doses Rounded to Available Vial Sizes in Critically Ill Pediatric Patients. J Pediatr Pharmacol Ther. 2017 Jan-Feb;22(1):15-21. doi: 10.5863/1551-6776-22.1.15. PMID: 28337077; PMCID: PMC5341527; cited in previous action.
73 Meister et al. (Comparison of low-molecular-weight heparin and antithrombin versus antithrombin alone for the prevention of symptomatic venous thromboembolism in children with acute lymphoblastic leukemia. Pediatr. Blood Cancer, 50: 298-303 (2008); hereafter “Meister”; cited in previous action)
74 Ting (Design of Dose Response Clinical Trials, Bass Conference XIII, 45 slides (6 Nov. 2006), also available at https://www.bassconference.org/tutorials/BASS%202006%20Ting.pdf (last visited 11/8/2022); hereafter “Ting”; cited in previous action).
75 Tourneau et al. (Dose escalation methods in phase I cancer clinical trials, J Natl Cancer Inst., vol. 101(10):708-20 (2009 May 20); hereafter “Tourneau”; cited in previous action)
76 Tahaineh et al. (Anti-factor Xa levels in obese patients receiving enoxaparin for treatment and prophylaxis indications. Clin Pharmacol. 2018 May 18;10:63-70. doi: 10.2147/CPAA.S161599. PMID: 29849468; PMCID: PMC5965377; hereafter “Tahaineh”; cited in previous action).
77 Konkle et al. (Use of recombinant human antithrombin in patients with congenital antithrombin deficiency undergoing surgical procedures. Transfusion, 43: 390-394 (2003); hereafter “Konkle; cited in previous action)
78 Gill et al., (Birth and developmental correlates of birth weight in a sample of children with potential sensory processing disorder, BMC Pediatr., 2013;13:29. Published 2013 Feb 25. doi:10.1186/1471-2431-13-29; hereafter “Gill”; cited in previous action)
79 Luciano (“World's Heaviest Man: The world begins to learn about Robert Earl Hughes", Washington Times Reporter; 13 March 2008, also available at https://web.archive.org/web/20120304152756/http://www.washingtontimesreporter.com/state_news/x688586179 (last visited 11/1/2022); hereafter “Luciano”; at page 1; cited in previous action)
80 Luciano (“World's Heaviest Man: Robert Earl Hughes becomes a star". Washington Times Reporter; 14 March 2008, also available at https://web.archive.org/web/20120304152843/http://www.washingtontimesreporter.com/state_news/x1993300104 (last visited 11/1/2022); hereafter “LucianoII”; at page 2; cited in previous action).