DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
The listing of claims filed 27 January 2025, are examined. Claims 1-20 are pending.
Claim Objections
Claims 1, 3-5, 12-14, and 20 are objected to because of the following informalities:
Claim 1 contains several grammatical and syntactical informalities that should be corrected for clarity and consistency. In step (c), the phrase: “Addition of a strong acid (that dissociates completely in water) to the solution obtained in Step (a) and simultaneously monitoring the decrease in the pH value of the solution until approximately pH 4.5 or less than pH 4.5 is reached” should preferably be recast in active process language, for example, “adding a strong acid … to the solution obtained in step (a) while simultaneously monitoring the decrease in pH until a pH of approximately 4.5 or lower is reached.” The existing formulation “approximately pH 4.5 or less than pH 4.5” is unnecessarily redundant.
In step (d), the phrase “Addition of tranexamic acid to reach the pH value of the solution obtained in Step (c) above the pH 2.0” is grammatically incorrect and obscures the intended relationship between TXA addition and increasing pH. The Detailed Description makes clear that the intended operation is addition of additional TXA to raise the pH of the acidified solution above pH 2.0. The claim should therefore preferably recite, for example, “adding tranexamic acid to raise the pH of the solution obtained in step (c) to above pH 2.0.” These defects are treated as minor informalities because the intended meaning is reasonably ascertainable from the specification.
Claims 3-5 recite “the initial concentration of tranexamic …”. The word “acid” appears to have been inadvertently omitted after “tranexamic.” The claims should be amended to recite “the initial concentration of tranexamic acid …”.
Claims 12-14 use the verb “raises” to describe the pH itself, e.g. “the pH value … raises …”. The grammatically appropriate expression is that the pH “rises” or “is raised.” For example, claim 12 should preferably recite “wherein the pH of the solution obtained in step (c) rises in step (d), upon addition of tranexamic acid, to above pH 2.5 …”, or “wherein the pH … is raised in step (d) by addition of tranexamic acid …”. Corresponding corrections should be made in claims 13 and 14.
Claim 20 contains several grammatical informalities. The expression “Addition of a strong acid … in drops” should preferably be written as “adding … the strong acid dropwise.” The expression “until approximately pH from 3.0 to 4.0 is reached” should preferably be amended to “until a pH in the range of approximately 3.0 to approximately 4.0 is reached.” Likewise, step (d) should preferably recite “adding tranexamic acid to raise the pH … to a value in the range of approximately 3.5 to approximately 4.5.” Appropriate correction is advised.
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 Applicant regards as his invention.
Claims 10, 19 and 20 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, regards as the invention.
Claim 1 expressly requires “a strong acid (that dissociates completely in water)”. The claim itself supplies a parenthetical definition requiring the acid to dissociate completely in water. Claim 10, however, depends from claim 1 and recites that “said strong acid” may be selected from “hydrochloric acid, perchloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, chloric acid, and phosphoric acid.” Likewise, dependent claim 20 incorporates all limitations of claim 1 but again expressly lists phosphoric acid among the permitted “strong acid[s].”
The claim language is internally inconsistent because phosphoric acid is not an acid that dissociates completely in water. Under conventional acid-base terminology, phosphoric acid is a weak polyprotic acid exhibiting equilibrium ionization rather than complete dissociation.
The specification does not resolve the inconsistency. Rather, the Detailed Description repeats both propositions: it describes the acid used in the method as a “strong acid” within the framework of claim 1, yet expressly lists phosphoric acid among the alleged strong acids.
Accordingly, it is unclear whether the parenthetical definition in claim 1 controls, such that phosphoric acid is excluded notwithstanding its express recitation in claims 10 and 20; the applicant intends to redefine the term “strong acid” in a nonconventional manner that includes phosphoric acid; or the inclusion of phosphoric acid is erroneous. Because these constructions result in different claim scope, the claims do not provide the degree of clarity required by 35 U.S.C. §112(b).
The applicant may overcome the rejection, for example, by deleting phosphoric acid from the recited alternatives, by removing or appropriately revising the parenthetical definition in claim 1 if supported by the original disclosure, or by otherwise defining the intended acid class with objective chemical language consistent throughout the claims and specification.
Claim 19 depends from claim 18. Claim 18 requires “the desired concentration of tranexamic acid in the final solution is approximately 400 mg/mL.” By virtue of its dependency, claim 19 incorporates that limitation. Claim 19 then recites “wherein the desired concentration of tranexamic acid in the final solution is approximately 450 mg/mL.” Thus, the same “desired concentration” is required by the claim to be both approximately 400 mg/mL and approximately 450 mg/mL.
The specification does not provide an unambiguous construction that resolves this inconsistency. To the contrary, the specification states that “about” and “approximately” may, in one embodiment, denote values within 10% of the stated value, preferably within 5%, but also identifies numerous narrower tolerances and states that in other embodiments the terms may have a higher tolerance of variation depending on the experimental technique used.
Consequently, whether “approximately 400 mg/mL” and “approximately 450 mg/mL” overlap depends upon which disclosed tolerance is applied. For example at ±5%, approximately 400 mg/mL corresponds to approximately 380-420 mg/mL, whereas approximately 450 mg/mL corresponds to approximately 427.5-472.5 mg/mL, resulting in no overlap; whereas at ±10%, approximately 400 mg/mL corresponds to approximately 360-440 mg/mL, and approximately 450 mg/mL corresponds to approximately 405-495 mg/mL, resulting in an overlapping interval. The specification does not identify which tolerance governs claim 19.
The issue is therefore not merely that the term “approximately” is a term of degree. Terms of degree are permissible where the specification or the knowledge of a skilled artisan supplies an objective standard (see Interval Licensing LLC v. AOL, Inc., 766 F.3d 1364, 1370-72, 112 USPQ2d 1188, 1192-93 (Fed. Cir. 2014); MPEP §2173.05(b)). Rather, the problem here is that the incorporated limitations themselves identify two materially different numerical targets and the specification supplies multiple potentially controlling tolerances, such that the boundaries of the dependent claim cannot be determined with reasonable certainty. A concentration cannot simultaneously be approximately 400 mg/mL and approximately 450 mg/mL, creating an internal inconsistency and rendering the scope of claim 19 unclear.
The applicant may overcome the rejection by amending claim 19 to establish an unambiguous dependency and concentration limitation. If approximately 450 mg/mL is intended as an alternative species within the broader range of claim 17, one suitable correction would be to rewrite claim 19 to depend directly from claim 17 rather than claim 18, subject to confirmation that such amendment is consistent with the applicant’s intended claim structure and does not introduce new matter.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. § 112(d):
(d) REFERENCE IN DEPENDENT FORMS.-Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. § 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. § 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 19 is rejected under 35 U.S.C. § 112(d) or pre-AIA 35 U.S.C. § 112, 4th paragraph, as being of improper dependent form for failing to specify a further limit of the subject matter of the claim upon which it depends.
Claim 18 recites, “wherein the desired concentration of tranexamic acid in the final solution is approximately 400 mg/mL.” Claim 19 depends from claim 18 and recites, “wherein the desired concentration of tranexamic acid in the final solution is approximately 450 mg/mL.” Claim 19 does not further limit claim 18, it rather attempts to substitute a different final concentration (i.e., approximately 450 mg/mL) for the approximately 400 mg/mL required by claim 18.
The terms “approximately 400 mg/mL” and “approximately 450 mg/mL” are not the same, and under the broadest reasonable interpretation in light of the specification, “approximately 400 mg/mL” would not reasonably encompass 450 mg/mL. The difference is about 12.5%, which is not a minor or customary variation absent a definition or teaching in the specification that “approximately 400 mg/mL” includes such a value.
Because claim 19 does not narrow or further limit the concentration required by claim 18, but instead contradicts or changes that limitation, claim 19 is not a proper dependent claim under 35 U.S.C. § 112(d). The applicant may overcome this rejection by, for example, amending claim 19 to depend from a claim that does not require approximately 400 mg/mL, or by amending the concentration in claim 19 to be a further limitation of approximately 400 mg/mL, if supported by the specification.
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.
For this analysis, a person of ordinary skill is a pharmaceutical formulation or process scientist with at least a bachelor’s degree in pharmacy, pharmaceutical chemistry, chemical engineering, or a related discipline and approximately two to five years of experience preparing aqueous drug or amino-acid formulations; additional education may substitute for experience. Such a person would understand acid-base equilibria, pKa, pH measurement, salt formation, solution compounding, and ordinary endpoint control.
Claims 1, 6, and 10-14 are rejected under 35 U.S.C. § 103 as being unpatentable over Jacobsen and Dubois (US20200078326A1; published 12 March 2020, hereinafter “Jacobsen”), in view of Kastrup et al. (US20160317434A1; published 03 November 2016, hereinafter “Kastrup”), and further in view of Hasegawa et al. (US6329548B1; published 11 December 2001, hereinafter “Hasegawa”).
Jacobsen teaches an aqueous tranexamic acid (TXA) compounding method. The process introduces approximately 90% of the batch water for injection into a compounding vessel, adds TXA "in divided portions until complete dissolution," and then adjusts pH with a pH adjuster (¶[0090]). Jacobsen therefore teaches initially dissolving TXA in water and making successive TXA additions while observing whether dissolution is complete.
Jacobsen also teaches measured-pH endpoint control. It states that acids and bases are added "on an as needed basis in order to achieve a desired pH"; when measured pH exceeds the desired value, an acid is used to lower the pH. Suitable acids expressly include hydrochloric, phosphoric, sulfuric, and nitric acid, with HCl specifically identified for pH adjustment (¶[0047]). Jacobsen's Example 5 prepared aqueous TXA solutions whose initial pH values included 4.0 and 5.0, using HCl or NaOH (¶[0130]). Thus, pH measurement, monitoring, and acid-controlled termination at a selected endpoint were conventional operations in aqueous TXA compounding.
Jacobsen does not expressly teach acidifying to pH 4.5 or lower for the purpose of increasing TXA solubility. Kastrup supplies direct TXA-specific acidification. Kastrup added 6 M HCl to 0.5 M neutrally charged TXA "until pH 4.3" to convert TXA to its protonated form, and then lyophilized the acidified solution (¶[0047]). Kastrup therefore teaches the same solute, an aqueous strong-acid addition, pH monitoring to an endpoint below 4.5, and protonation of TXA.
Hasegawa supplies the reason to use that acidification when higher aqueous loading is desired. Hasegawa identifies its objective as increasing lysine solubility in an aqueous lysine solution and obtaining a high-concentration liquid composition (col. 3, ll. 27-46). Hasegawa found that adding an acid radical derived from HCl or sulfuric acid at a predetermined ratio to aqueous lysine increased lysine solubility relative to the acid-free lysine solution (col. 3, ll. 47-65). Example 2 reports, at 30 °C, 160 g lysine/100 g water at 0% HCl/lysine molar ratio, 175 g/100 g water at 22.8%, and 179 g/100 g water at 26%; at 35%, solubility returned to 160 g/100 g water (Table 2). Hasegawa further directs the skilled person to measure solubility as a function of acid content and plot the relationship to determine a desired acid-to-lysine range (col. 4, ll. 43-58).
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, seeking to increase the amount of TXA dissolved during Jacobsen's divided-portion compounding to apply Kastrup's TXA-specific HCl protonation and Hasegawa's known acid/amino-acid solubility-control technique. One would be motivated to do so because Jacobsen teaches a water-based TXA compounding process with divided TXA additions until complete dissolution, and pH measurement/adjustment using HCl, NaOH, phosphoric acid, sulfuric acid, or nitric acid (¶[0047], ¶[0090], ¶[0130]); Kastrup teaches direct TXA/HCl acidification (6 M HCl was added to aqueous TXA until pH 4.3 to convert TXA to its protonated form; ¶ [0047]); and Hasegawa identifies increasing amino acid aqueous solubility as a problem and teaches that adding an acid radical derived from HCl or sulfuric acid at a selected acid-to-amino-acid ratio can increase solubility (col. 3, ll. 27-65; col. 4, ll. 43-58; Table 2).
Adding further amphoteric TXA to an acidic solution provides additional proton-accepting amino functionality, predictably changes the acid-to-solute ratio, and raises the pH relative to the fixed-acid condition. A skilled formulator therefore would have monitored pH after each additional TXA portion and added further HCl when necessary to restore the selected acidic solubilizing condition before charging still more TXA. Repetition would continue until the desired amount was dissolved.
A person of ordinary skill seeking to increase the amount of TXA dissolved in Jacobsen’s divided-portion method would therefore have had a concrete reason to use Kastrup’s HCl protonation and Hasegawa’s acid-to-amino-acid solubility technique. Under KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 406, 415-18 (2007), the combination uses known elements for their established functions: HCl acidification to protonate TXA by Kastrup; pH monitoring to control the extent of protonation by Jacobsen and Kastrup; acid-to-amino-acid ratio to control solubility by Hasegawa; and divided TXA addition with dissolution monitoring by Jacobsen. Thus, the combination is a predictable use of prior art elements according to their established functions. The modification uses a known technique to improve a similar method in the same way and applies a known technique to a process ready for improvement to obtain the technique's predictable function (see MPEP § 2143(I)(C)-(D)).
A reasonable expectation existed because the cited references do not merely speculate; they demonstrate the relevant steps: Jacobsen dissolved TXA in water using divided additions; Kastrup acidified aqueous TXA with HCl to pH 4.3 and protonated TXA; and Hasegawa measured increased lysine solubility at selected HCl/lysine ratios, taught how to determine a desired solubility range, and experimentally demonstrated an operative acid/amino-acid region that increased aqueous solubility and taught how to locate that region. The expectation would have been that acid addition would perform its known protonating and solubility-control functions. Therefore, a person of ordinary skill would have reasonably expected that adding HCl to an aqueous TXA solution, monitoring pH, and controlling the acid-to-TXA ratio would allow further TXA to be dissolved.
Regarding instant claim 6, which requires lowering the solution to approximately pH 4.0. Jacobsen expressly prepared aqueous TXA at initial pH 4.0 using HCl or NaOH (¶[0130]), and Kastrup selected pH 4.3 for HCl-protonated TXA (¶[0047]). The claimed value is therefore expressly taught as an aqueous TXA pH and immediately adjacent to a TXA/HCl protonation endpoint. pH was known to be result-effective because Kastrup links pH to TXA protonation and Hasegawa links acid ratio to solubility. Selecting approximately pH 4.0 for the acidification step would have been an obvious working point within the known pH/protonation variable as a matter of routine optimization of a recognized result-effective variable (see In re Aller, 220 F.2d 454, 456 (CCPA 1955); In re Applied Materials, Inc., 692 F.3d 1289, 1295-97 (Fed. Cir. 2012); MPEP § 2144.05(II)).
Regarding instant claim 10 which recites a list of alternative strong acids that includes HCl, Jacobsen identifies HCl, phosphoric acid, sulfuric acid, and nitric acid as suitable TXA-solution pH adjusters (¶[0047]), and Kastrup actually uses HCl to acidify TXA (¶[0047]). The selection of HCl satisfies the instant alternative limitation and is obvious.
Regarding instant claim 11, which recites a strong-acid concentration of approximately 0.01-10.00 eq/L, Kastrup uses 6 M HCl (¶[0047]). Because HCl is monoprotic, 6 M HCl provides 6 equivalents/L, which is directly within the instant claimed range. The claimed range overlaps a prior-art value, and is therefore obvious (see In re Peterson, 315 F.3d 1325, 1329-30 (Fed. Cir. 2003); MPEP § 2144.05(I)
Regarding instant claim 12, which alternatively requires the pH after an additional TXA charge to be above 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, or 5.5, Kastrup's aqueous TXA/HCl system reaches pH 4.3 (¶[0047]). Thus, satisfying at least the instant claimed alternatives above 2.5, 3.0, 3.5, and 4.0. Jacobsen independently prepared aqueous TXA at pH 5.0, 6.0, and higher (¶[0130]), satisfying the remaining instant claimed threshold alternatives as operative aqueous-TXA conditions. For the reasons stated for instant claim 1, using the pH reached after a TXA portion as the feedback endpoint before readjustment with acid would have been a predictable implementation of the combined teachings.
Regarding instant claim 13, which requires raising pH after TXA addition to approximately pH 3.5, Kastrup identifies pH 4.3 as an operative HCl/TXA protonation condition (¶[0047]). Jacobsen identifies pH 4.0 as an operative aqueous TXA condition (¶[0130]), and Hasegawa directs the worker to vary the acid/solute relationship and determine the desired solubility region experimentally (col. 4, ll. 43-58). Because pH and acid-to-solute ratio were recognized result-effective variables, known to affect protonation and solubility, selecting a slightly more acidic working point, such as approximately pH 3.5, would have been routine optimization of a known result-effective condition (see In re Aller, 220 F.2d 454, 456 (CCPA 1955); In re Applied Materials, Inc., 692 F.3d 1289, 1295-97 (Fed. Cir. 2012); MPEP § 2144.05(II)).
Regarding instant claim 14, which requires the post-TXA-addition pH to exceed 4.5, Jacobsen expressly identifies pH 5.0, 6.0, 6.5, 7.0, and higher as operative initial pH values for aqueous TXA (¶[0130]). Allowing an added TXA portion to raise the solution above 4.5, followed by acid readjustment as required by instant claim 1, would have been a predictable feedback-control choice within Jacobsen’s known aqueous TXA pH conditions.
Claims 1, and 2-5 are rejected under 35 U.S.C. § 103 as being unpatentable over Jacobsen and Dubois (US20200078326A1; published 12 March 2020, hereinafter “Jacobsen”), in view of Kastrup et al. (US20160317434A1; published 03 November 2016, hereinafter “Kastrup”), and further in view of Hasegawa et al. (US6329548B1; published 11 December 2001, hereinafter “Hasegawa”), and Kane et al. (Physiologically based modelling of tranexamic acid pharmacokinetics, Eur. J. Pharm. Sci. 164:105893 (2021); hereinafter “Kane”).
Jacobsen, in view of Kastrup, and in further view of Hasegawa, teach the limitations of instant claim 1, as described above, from which instant claims 2-5 depend, however do not explicitly teach the specific limitations of instant claims 2-5.
Kane reports that TXA is a zwitterionic compound having an aqueous solubility of 167 mg/mL in water (Results §3, first paragraph following Figure 1). That reported water-solubility concentration lies within each of instant claim 2's 120-200 mg/mL, instant claim 3's 130-180 mg/mL, and instant claim 4's 150-170 mg/mL initial ranges. The prior-art value therefore overlaps each instant claimed range and are rendered obvious (In re Peterson, 315 F.3d 1325, 1329-30 (Fed. Cir. 2003); MPEP § 2144.05(I)).
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to select Kane’s reported water-solubility concentration as a logical starting point for the process of instant claim 1, because it loads a large initial amount of TXA while remaining at a known water-soluble concentration. The subsequent acid-assisted incremental loading of Jacobsen/Kastrup/Hasegawa could then be used to increase the total dissolved amount. Kane reports an actual measured solubility, therefore, starting at 167 mg/mL in water would have been expected to succeed.
Instant claim 5 recites approximately 165 mg/mL. Kane's 167 mg/mL value differs by about 1.2%, and the claim expressly uses "approximately." In the absence of demonstrated criticality between 165 and 167 mg/mL, choosing approximately 165 mg/mL as the initial solution would have been an obvious concentration at the known aqueous-solubility region (see In re Aller, 220 F.2d 454, 456 (CCPA 1955)).
Claims 1, and 7-9 are rejected under 35 U.S.C. § 103 as being unpatentable over Jacobsen and Dubois (US20200078326A1; published 12 March 2020, hereinafter “Jacobsen”), in view of Kastrup et al. (US20160317434A1; published 03 November 2016, hereinafter “Kastrup”), and further in view of Hasegawa et al. (US6329548B1; published 11 December 2001, hereinafter “Hasegawa”), and Tuominen et al. (US4661606A; published 28 April 1987, hereinafter “Tuominen”).
Jacobsen, in view of Kastrup, and in further view of Hasegawa, teach the limitations of instant claim 1, as described above, from which instant claims 7-9 depend, however do not explicitly teach the specific limitations of instant claims 7-9.
Tuominen concerns aqueous processing and extraction of amino acids rather than pharmaceutical formulation of TXA (Abstract). It is nevertheless reasonably pertinent to the problem addressed by instant claims 7-9, selecting strongly acidic aqueous conditions to control whether an amino/carboxylic-acid compound is present as a zwitterion or an acid salt. Tuominen explains that aqueous pH is controlled so amino acids are not present as zwitterions and identifies strong water-soluble mineral acids including HCl, nitric, sulfuric, hydrobromic, and phosphoric acids (col. 5, ll. 30-47). Kastrup independently establishes the pertinence to TXA by deliberately converting TXA to its protonated form with HCl (¶[0047]). Tuominen is therefore reasonably pertinent to the particular protonation/pH problem (see In re Bigio, 381 F.3d 1320, 1325 (Fed. Cir. 2004); MPEP § 2141.01(a)).
Regarding instant claims 7 and 8, Tuominen teaches that, when an anionic extractant is used, the acidic aqueous stripping phase is maintained at pH less than 0.5 and that the amino acid is recovered in the aqueous phase as an acid salt, such as a hydrochloride (col. 8, ll. 1-21). Thus, a pH below 4.0 and, specifically, below 0.5 was a known operative strong-acid aqueous condition for amino-acid protonation/partitioning.
In view of Kastrup's direct HCl protonation of TXA and Hasegawa's teaching that acid-to-amino-acid ratio controls aqueous solubility, it would have been obvious to investigate and select a lower pH, including below 4.0 or below 0.5, when a more strongly protonating condition was desired. Tuominen's pH below 0.5 directly meets at least one alternative of instant claim 8.
Instant claim 9 requires approximately pH 0.2. Tuominen's Example IV, Series A, prepared a 15 mL aqueous tryptophan phases whose acid pH values were achieved with HCl and reports an actual pH of 0.18. Approximately pH 0.18 is effectively the instant claimed approximately pH 0.2, rendering the instant claim obvious (see In re Peterson, 315 F.3d 1325, 1329-30 (Fed. Cir. 2003)).
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to apply that known highly protonating amino-acid condition to the Kastrup/Hasegawa acidification technique when seeking a more fully protonated TXA condition, because the references collectively identify the same strong-acid control mechanism (see KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417-418 (2007)). A reasonable expectation existed that the low pH would protonate the amino functionality. A person of ordinary skill seeking a more strongly protonating condition for TXA would have been motivated to combine Tuominen’s low-pH acid-salt teaching with the acid-solubility technique of Hasegawa.
Tuominen demonstrates that amino acids can be maintained as acid salts at pH below 0.5, and Kastrup demonstrates that TXA is protonated by HCl. Although Hasegawa shows a bounded optimum for lysine solubility, a person of ordinary skill would still reasonably expect that lowering pH to Tuominen’s disclosed condition would protonate TXA. The reasonable expectation is not that pH 0.2 must maximize solubility, rather it is that the acidification would perform its known protonation function.
Claims 1, and 15-19 are rejected under 35 U.S.C. § 103 as being unpatentable over Jacobsen and Dubois (US20200078326A1; published 12 March 2020, hereinafter “Jacobsen”), in view of Kastrup et al. (US20160317434A1; published 03 November 2016, hereinafter “Kastrup”), and further in view of Hasegawa et al. (US6329548B1; published 11 December 2001, hereinafter “Hasegawa”), Larsen et al. (US20110021964A1; published 27 January 2011, hereinafter “Larsen”), and Baylis et al. (Topical tranexamic acid inhibits fibrinolysis more effectively when formulated with self-propelling particles, J. Thromb. Haemost. 17:1645-1654 (2019); hereinafter “Baylis”).
Jacobsen, in view of Kastrup, and in further view of Hasegawa, teach the limitations of instant claim 1, as described above, from which instant claims 15-19 depend, however do not explicitly teach the specific limitations of instant claims 15-19.
Larsen concerns fluid or liquid pharmaceutical compositions for hemostasis and wound healing. It provides a printing reservoir containing one or more bioactive agents in solubilized form or suspension (¶[0024]). It states that bioactive agents may be used at any suitable pharmaceutically relevant concentration (¶[0168]) and expressly enumerates 200-300, 300-400, 400-500, and 500-600 mg/mL subranges for the bioactive agent in the fluid or liquid composition (¶[0174]). Larsen identifies anti-fibrinolytic agents including TXA and states that, in a preferred embodiment, TXA is included if an anti-fibrinolytic agent is present (¶[0191]). Larsen further teaches a composition comprising a solvent and a bioactive agent, with the solvent or fluid component being an aqueous medium, optionally saline (¶[0289]-[0290]).
Therefore, Larsen would have suggested selecting TXA as an anti-fibrinolytic bioactive agent, water as the solvent, and a concentration within the 200-600 mg/mL region. Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, following the Jacobsen/Kastrup/Hasegawa process to pursue Larsen's high concentrations for aqueous TXA. Larsen's purpose was to apply a small, controlled liquid amount while reducing swelling and avoiding waste of pharmaceutical composition (¶[0015]), wherein increasing dissolved drug concentration predictably delivers more TXA per unit liquid and advances that stated objective. Jacobsen supplies portionwise aqueous TXA compounding and pH control, Kastrup supplies direct HCl protonation of TXA, Hasegawa supplies the acid/amino-acid solubility technique, and Larsen supplies the relevant aqueous TXA concentration targets. The proposed combination therefore uses each teaching for its known function and is supported by a design incentive (see KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416-418 (2007); MPEP § 2143(I)(A), (C), and (D)).
Baylis corroborates that a concentrated, protonated TXA species could actually be dissolved in water. Baylis prepared TXA-HCl by adding concentrated HCl to 0.5 M TXA and lyophilizing, and then dissolved 8 g of TXA-HCl in water at 300 mg/mL for swine-gauze experiments (p. 1647, §2.1). Baylis does not disclose 300 mg/mL free-base-equivalent TXA and does not reach 400 mg/mL, but it experimentally demonstrates a 300 mg/mL aqueous acid-form TXA material. Together with Kastrup's direct TXA protonation and Hasegawa's experimental acid-enhanced amino-acid solubility, that demonstration would have provided a reasonable expectation of sucess that incremental acid-assisted loading toward Larsen's neighboring 300-400 and 400-500 mg/mL ranges could succeed (see In re O’Farrell, 853 F.2d 894, 903–04 (Fed. Cir. 1988); MPEP § 2143.02).
Regarding instant claim 15, which alternatively requires a final concentration above 160, above 250, or above 350 mg/mL. Larsen teaches 200-300, 300-400, 400-500, and 500-600 mg/mL bioactive-agent ranges (¶[0174]), identifies TXA as a preferred anti-fibrinolytic component (¶[0191]), and identifies an aqueous solvent (¶[0289]-[0290]). Values in the 400-500 mg/mL range satisfy every alternative threshold in instant claim 15. The claimed thresholds therefore overlap or are encompassed by the expressly taught ranges, and are therefore obvious (see In re Peterson, 315 F.3d 1325, 1329-30 (Fed. Cir. 2003)).
Instant claim 16 requires a final TXA concentration above 400 mg/mL. Larsen's teaches 400-500 mg/mL interval contains concentrations above 400 mg/mL (¶[0174]). Selecting TXA and an aqueous medium as taught in ¶[0191] and ¶[0289]-[0290], and using the acid-assisted incremental loading of the primary combination, would have yielded the instant claimed concentration range as an overlapping selection (see In re Peterson, 315 F.3d 1325, 1329-30 (Fed. Cir. 2003) and Merck & Co. v. Biocraft Labs, Inc., 874 F.2d 804, 807 (Fed. Cir. 1989)). The prima facie obviousness case depends on the relevant 400-500 mg/mL subrange being reasonably suggested for TXA and on the combined protonation/solubility evidence supplying a reasonable expectation of attaining it.
Regarding instant claim 17, which recites approximately 200-600 mg/mL or 300-500 mg/mL, Larsen teaches 200-300, 300-400, 400-500, and 500-600 mg/mL intervals (¶[0174]). Those intervals overlap and collectively span the instant claimed alternatives and applying them to TXA in an aqueous medium would have been obvious for the reasons stated above (see In re Peterson, 315 F.3d 1325, 1329-30 (Fed. Cir. 2003)).
Instant claim 18 requires approximately 400 mg/mL. Larsen expressly identifies adjacent 300-400 and 400-500 mg/mL intervals, each meeting at 400 mg/mL (¶[0174]). Approximately 400 mg/mL is therefore an expressly identified concentration boundary. Selection of that value for aqueous TXA would have been prima facie obvious from Larsen’s ¶[0191] and ¶[0289]-[0290] and combined with the acid-assisted solubilization teachings as a matter of routine optimization of a known concentration range (see In re Aller, 220 F.2d 454, 456 (CCPA 1955)). The prima facie case obviousness case rests on the relevant 400-500 mg/mL subrange being reasonably suggested for TXA and on the combined protonation/solubility evidence supplying a reasonable expectation of attaining it.
To the extent instant claim 19 is construed as requiring approximately 450 mg/mL notwithstanding its dependency from claim 18, Larsen's 400-500 mg/mL interval contains 450 mg/mL (¶[0174]). The claimed value is therefore enclosed by a prior-art range, and is therefore obvious (see In re Peterson, 315 F.3d 1325, 1329-30 (Fed. Cir. 2003)). The motivation and expectation are the same as for instant claims 16 and 18, wherein more drug per unit aqueous carrier meets Larsen's low-liquid/waste objective, and Kastrup, Hasegawa, and Baylis supply the acid-form and solubility evidence.
Claims 1, and 20 are rejected under 35 U.S.C. § 103 as being unpatentable over Jacobsen and Dubois (US20200078326A1; published 12 March 2020, hereinafter “Jacobsen”), in view of Kastrup et al. (US20160317434A1; published 03 November 2016, hereinafter “Kastrup”), and further in view of Hasegawa et al. (US6329548B1; published 11 December 2001, hereinafter “Hasegawa”), Kane et al. (Physiologically based modelling of tranexamic acid pharmacokinetics, Eur. J. Pharm. Sci. 164:105893 (2021); hereinafter “Kane”), Larsen et al. (US20110021964A1; published 27 January 2011, hereinafter “Larsen”), and Baylis et al. (Topical tranexamic acid inhibits fibrinolysis more effectively when formulated with self-propelling particles, J. Thromb. Haemost. 17:1645-1654 (2019); hereinafter “Baylis”).
Jacobsen, in view of Kastrup, and in further view of Hasegawa, teach the limitations of instant claim 1, as described above, from which instant claim 20 depends, however do not explicitly teach the specific limitations of instant claims 20.
Kane reports an aqueous TXA solubility of 167 mg/mL in water, within claim 20's approximately 120-200 mg/mL initial concentration (Results §3, first paragraph following Figure 1). Jacobsen teaches introducing water into a compounding vessel, adding TXA in divided portions until complete dissolution, and adjusting measured pH with acid or base as needed (¶[0047], ¶ [0090]). Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to start at Kane's known water-solubility concentration and use Jacobsen's measured-pH, portionwise-compounding controls (see In re Peterson, 315 F.3d 1325, 1329-30 (Fed. Cir. 2003)).
Instant claim 20's acid list includes HCl. Jacobsen identifies HCl for TXA-solution pH adjustment ¶[0047]) and prepared an aqueous TXA solution adjusted to pH 4.0 using HCl or NaOH (¶[0130]), and Kastrup adds 6 M HCl to aqueous TXA until pH 4.3 (¶[0047]). Thus, the upper HCl range of instant claim 20's approximately pH 3.0-4.0 interval were known for aqueous TXA and the lower range is a routine variation within the recognized result-effective pH/protonation variable (see In re Aller, 220 F.2d 454, 456 (CCPA 1955); In re Applied Materials, Inc., 692 F.3d 1289, 1295-97 (Fed. Cir. 2012)).
Neither Jacobsen nor Kastrup literally requires one-drop-at-a-time acid addition. Jacobsen, however, adds acid only as needed to reach a measured pH endpoint (¶[0047]), and Hasegawa expressly discusses HCl being gradually added as acid-to-lysine ratio changes (col. 4, ll. 30-42). Using smaller acid aliquots, including drops, near a pH endpoint would have been a predictable way to avoid overshoot while performing the taught endpoint-controlled addition. No different function is attributed to a "drop" than to a small aliquot, thus is obvious (see KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007)).
Kastrup's HCl/TXA endpoint of pH 4.3 lies within instant claim 20's approximately pH 3.5-4.5 interval (¶[0047]). Jacobsen adds TXA in divided portions until dissolution (¶[0090]). For the reasons stated for instant claim 1, adding another amphoteric TXA portion to the acidic liquid predictably changes the proton/solute ratio and raises pH, and monitoring until pH lies in the known 3.5-4.5 protonated-TXA region, then adding acid to restore the lower endpoint and repeating, would have been a predictable feedback control implementation of Jacobsen, Kastrup, and Hasegawa (see In re Keller, 642 F.2d 413, 425 (CCPA 1981)). While the references do not literally state "acid, then TXA, then acid, then TXA", the sequence is an inferred process-control arrangement based on Jacobsen's repeated TXA portions and Kastrup/Hasegawa's acid-to-solute adjustment, in which the combined teachings suggest.
Larsen teaches 200-300, 300-400, and 400-500 mg/mL bioactive-agent ranges (¶[0174]), identifies TXA as a preferred anti-fibrinolytic component (¶[0191]), and identifies aqueous solvent (¶[0289]-[0290]). Those ranges overlap with instant claim 20's approximately 250-450 mg/mL final interval. Baylis experimentally dissolved TXA-HCl in water at 300 mg/mL (p. 1647, §2.1), a value within the claimed interval, and thereby corroborates a reasonable expectation for the acid-form portion of the range.
Thus, it would have been prima facie obvious to one of ordinary skill in the art, prior to the instant effective filing date, to continue the divided TXA/acid loading until a Larsen concentration within the overlapping interval was reached because higher dissolved concentration delivers more TXA per unit liquid and advances Larsen's objective of reducing liquid-associated swelling and waste (¶[0015]). The overlap supports a prima facie case of obviousness (see In re Peterson, 315 F.3d 1325, 1329-30 (Fed. Cir. 2003)).
In summary, Jacobsen provides the aqueous divided-portion TXA process and pH control, Kastrup provides direct HCl protonation of TXA to pH 4.3, Hasegawa provides acid-to-amino-acid solubility control and directs experimental selection of the ratio, Kane provides a known initial TXA water-solubility value, Tuominen provides low-pH amino acid acid-salt conditions, Larsen provides express high-concentration TXA targets and objective motivation, and Baylis provides a demonstrated 300 mg/mL TXA-HCl solution. Thus instant claims 1-20 would have been obvious to a person of ordinary skill with a reasonable expectation of success.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to REBECCA L. SCOTLAND whose telephone number is (571) 272-2979. The examiner can normally be reached M-F 9:00 am to 5:00 pm EST.
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, Robert A. Wax can be reached at (571) 272-0623. 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.
/RL Scotland/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
Prosecution Insights