DETAILED ACTION
This office action is in response to applicant’s filing dated January 22, 2026.
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 .
Status of Claims
Claims 1-16 are pending in the instant application. Acknowledgement is made of Applicant's remarks and amendments filed January 22, 2026. Acknowledgement is made of Applicant's amendment of claims 1-9.
Applicants elected without traverse Group I, drawn to a pharmaceutical composition comprising a liquid composition containing p-boronophenylalanine, wherein the liquid composition is accommodated in a packaging material as the elected invention and a formulation containing L-BPA (boronophenylalanine); D-sorbitol, sodium hydroxide, hydrochloric acid as a pH adjuster, and sodium hydrogen sulfite as an antioxidant in water as the elected formulation species and polyethylene resin as the elected thermoplastic resin species in the reply filed on July 7, 2025. The requirement is still deemed proper. Claims 9-16 remain withdrawn.
Claims 1-8 are presently under examination as they relate to the elected species:
L-BPA (boronophenylalanine); D-sorbitol, sodium hydroxide, hydrochloric acid as a pH adjuster, and sodium hydrogen sulfite as an antioxidant in water as the elected formulation species and polyethylene resin
Priority
The present application is a 371 of PCT/JP2020/034391 filed on September 11, 2020, which claims benefit of foreign priority to JAPAN 2019-165835 filed on September 12, 2019.
Objections and/or Rejections and Response to Arguments
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
New Objections and/or Rejections
Necessitated by Claim Amendment
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 and 5-8 are rejected under 35 U.S.C. 103 as being unpatentable over Nakajima et al (JP2013173804, cited in the IDS filed September 28, 2023) in view of Kulvik et al (European Journal of Pharmaceutical Sciences, 2003; 18:155–163, cited in a previous Office Action); Waterman et al (Pharmaceutical Development and Technology, 2002; 7(1):1–32, cited in a previous Office Action); and Gustafsson et al (US 6,398,771 B1, cited in a previous Office Action).
Regarding claims 1 and 5-8, Nakajima teaches a liquid composition comprising p-boronophenylalanine, sorbitol, and sulfite (claim 1); wherein the sorbitol is D-sorbitol (claim 2), wherein the pH is in the range of 6.5 to 7.5 (claim 3); the liquid composition is preferably an aqueous liquid [0021]. Nakajima teaches sulfite is an antioxidant [0039]. Nakajima teaches as long as the composition of the present invention is not contrary to the object of the present invention, other components used in the technical field can be contained as necessary; examples of such components include pH adjusters such as hydrochloric acid and sodium hydroxide [0033].
Nakajima is silent with regard to dissolving oxygen in the liquid composition; thus, it is safe to assume that the composition does not contain dissolved oxygen. A composition wherein oxygen is not dissolved in the composition would read on a concentration of dissolved oxygen in the liquid is 3.0 ppm or less. Similarly, with regard to claim 2, Nakajima is silent with regard to further addition of tyrosine; thus it is safe to assume the composition does not contain tyrosine. Thus, the composition of Nakajima reads on a composition that comprises 0.75 mass% or less of tyrosine.
MPEP 2131.03 states:
"[W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art." Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (citing In re Petering, 301 F.2d 676, 682, 133 USPQ 275, 280 (CCPA 1962)).
Nakajima does not explicitly teach the liquid composition is in a kit comprising packaging material. The Examiner notes that instant specification teaches the state that the liquid composition containing BPA is accommodated in a packing material means that the packaging material contains the liquid composition containing BPA and is sealed, see [0044], and the packaging material maybe in a bag shape a box shape, and a bottle shape, preferably the packaging material is for an infusion bag, see [0048]. By broadest reasonable interpretation, any container reads on a packaging material. The composition taught by Nakajima is a liquid and would require to be in vial or container to hold the liquid. Nakajima does not explicitly teach the container is sealed. Moreover, Nakajima does not explicitly teach the liquid composition is in bag-shaped packaging material; wherein the packaging material comprises thermoplastic resin comprising the thermoplastic resin of claim 7, or wherein the packaging material is an infusion bag.
However, Kulvik teaches boron neutron capture therapy (BNCT) is an experimental therapy combining a boron pharmaceutical with neutron irradiation; it is being used for treatment of patients with malignant gliomas and cutaneous melanoma; currently, among various synthetic boron compounds only two pharmaceuticals are used in clinical BNCT; including 4-boronophenylalanine, BPA (page 155); L-phenylalanine and L-tyrosine are residual impurities of L-BPA (abstract); L-BPA is split to boric acid and L-phenylalanine (Phe) or L-tyrosine (Tyr); this loss of boric acid could occur through acid catalysed hydrolysis of the B–C bond (Phe) or by oxidative cleavage of the C–B bond (Tyr). Thus, Kulvik teaches tyrosine is a known impurity of boronophenylalanine and oxidation of boronophenylalanine converts boronophenylalanine to boric acid and L-tyrosine.
Waterman teaches sacrificial reductants are compounds that are oxidized more readily than the drug; the effectively scavenge oxygen while they are themselves consumed; this strategy can be especially effective in systems where the amount of oxygen present is limited due to packaging; for example, in a glass sealed system, the amount of oxygen is limited to the headspace and dissolved oxygen; examples of such antioxidants include sulfites (page 22, left, last paragraph).
Gustafsson teaches containers for parenteral fluids (title); a flexible transparent container for improved storage of oxygen sensitive parenterally administrable agents wherein the container comprises an inner, primary container enclosed in a substantially oxygen impermeable outer envelope with an oxygen absorber, capable of consuming essentially all residual oxygen after the outer envelope is sealed, as well as the oxygen penetrating said envelope wherein the inner container (claim 1); wherein the inner primary container is made of a multilayered film comprising an inner sealant layer containing polypropylene, a propylene ethylene copolymer or a mixture of polypropylene or polyethylene, and an interior layer containing a thermoplastic elastomer (claim 2); and an inner, sealant layer facing the medical fluid consisting of a mixture of a polyethylene/polypropylene copolymer and styrene/ethylene/ butadiene/styrene copolymer from Shell (a styrene/ethylene/butadiene/styrene (SEBS) copolymer (col 7, lines 49-54). Moreover, Gustafsson teaches according to a particular important embodiment of the present invention, the inner primary container is divided into two or more chambers by one or more leaktight seals which are possible to rupture by hand from the outside of the container when the contents of the chambers are desired to be mixed to a homogenous fluid and administered to a patient by infusion or injection; for this reason, the inner container is provided with a fluid communication port in its bottom through which the mixed product can be received and through which additional agents can be supplemented to either to the mixed product or to the agent stored in the lower chamber; the port is attachable to conventional infusion devices and other devices useful for parenteral administration (col 5, lines 21-36).
As such, since Nakajima teaches a liquid composition comprising p-boronophenylalanine, sorbitol, and sulfite wherein the composition is an injection; since Kulvik teaches boronophenylalanine is susceptible to oxidation; since Waterman teaches sacrificial reductants such as sulfites effectively scavenge oxygen while they themselves are consumed and this antioxidant strategy is particularly effective in systems where amount of oxygen is limited; and since Gustafsson teaches that it was known in the art that infusion bags made with an inner sealant layer containing polypropylene, a propylene ethylene copolymer or a mixture of polypropylene or polyethylene, and an interior layer containing a thermoplastic elastomer are suitable for storing oxygen sensitive compositions, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to utilize the infusion bag container taught by Gustafsson to store the composition taught by Nakajima with an expectation of success, since the prior art establishes that boronophenylalanine is susceptible to oxidation, sulfites are particularly effective antioxidants in systems where amount of oxygen is limited, and the storage containers of Gustafsson are useful for limiting oxygen exposure.
Regarding claim 3, the prior art does not explicitly teach the disclosed composition comprises a tyrosine content in the liquid composition after the pharmaceutical composition is stored at 40°C/75%RH for 2 weeks of 1.20 mass% or less in the case of Condition II. However, the above chemical and physical properties depend, among other things, from the specific components, relative amounts, type of formulation, and pH of the formulation etc., all of which seem to be the same or very similar to the composition taught by the prior art (see above rejection).
The office does not have the facilities and resources to provide the factual evidence needed in order to establish that the formulations of p-boronophenylalanine and an antioxidant, sulfite that will result from the teachings of the prior art does not possess the same material, structural and functional characteristics of the formulation claimed in the instant application. In the absence of evidence to the contrary, the burden is on the applicant to prove that the formulation used in the instantly claimed method is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Taken together, all this would result in the composition of claims 1-3 and 5-8 with a reasonable expectation of success.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Nakajima et al (JP2013173804, cited in the IDS filed September 28, 2023) in view of Kulvik et al (European Journal of Pharmaceutical Sciences, 2003; 18:155–163, cited in a previous Office Action); Waterman et al (Pharmaceutical Development and Technology, 2002; 7(1):1–32, cited in a previous Office Action); and Gustafsson et al (US 6,398,771 B1, cited in a previous Office Action) as applied to claims 1-3 and 5-8 above, and further in view of Rowe et al (Handbook of Pharmaceutical Excipients, 6th edition, 2009).
The combination of Nakajima, Kulvik, Waterman, and Gustafsson teach a liquid composition comprising p-boronophenylalanine, sorbitol, and sulfite, wherein the pH is in the range of 6.5 to 7.5, in a sealed infusion bag for injection. The cited art does explicitly teach the sulfite is the elected, sodium hydrogen sulfite.
However, as set forth above, Kulvik teaches tyrosine is a known impurity of boronophenylalanine and oxidation of boronophenylalanine converts boronophenylalanine to boric acid and L-tyrosine.
Waterman teaches sacrificial reductants are compounds that are oxidized more readily than the drug; the effectively scavenge oxygen while they are themselves consumed; this strategy can be especially effective in systems where the amount of oxygen present is limited due to packaging; for example, in a glass sealed system, the amount of oxygen is limited to the headspace and dissolved oxygen; examples of such antioxidants include sulfites (page 22, left, last paragraph).
Moreover, Rowe teaches sodium metabisulfite is widely used as an antioxidant in oral, parenteral, and topical pharmaceutical formulations (page 654, left 7 Applications in Pharmaceutical Formulation or Technology); sodium metabisulfite is used as an antioxidant at low pH, sodium bisulfite at intermediate pH, and sodium sulfite at higher pH values (page 655, right 18 Comments); sodium bisulfite synonym is sodium hydrogen sulfite. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to utilize sodium hydrogen sulfite as the sulfite in the composition taught by Nakajima, Kulvik, Waterman, and Gustafsson, since the prior art teaches a composition comprising boronophenylalanine and an antioxidant, a sulfite wherein the pH is in the range of 6.5 to 7.5 and sodium hydrogen sulfite is a known antioxidant utilized in pharmaceutical formulations having intermediate pH.
Taken together, all this would result in the composition of claim 4 with a reasonable expectation of success.
Response to Arguments
Applicant's arguments have been fully considered but are not persuasive.
Since a new rejection was issued (see above), it is the Examiner’s belief that most of the arguments presented by Applicant have been considered/answered in the rejection itself, so only those arguments not addressed in the rejection are being considered below:
Applicant argues:
Applicant has unexpectedly discovered that controlling the concentration of dissolved oxygen in a liquid composition containing BPA can inhibit changes in the liquid composition and prevent the liquid from becoming colored when the liquid is stored for a long period of time. The claimed pharmaceutical kit comprising a liquid composition that satisfies claim Condition I or Condition II can be obtained by accommodating the liquid composition in a packaging material (e.g., a packaging material as described at paragraphs 0044-0048 of the present application), and subsequently heat- sterilizing the pharmaceutical kit under an inert gas atmosphere.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
The Examiner notes that instant specification teaches the state that the liquid composition containing BPA is accommodated in a packing material means that the packaging material contains the liquid composition containing BPA and is sealed, see [0044], and the packaging material maybe in a bag shape a box shape, and a bottle shape, preferably the packaging material is for an infusion bag, see [0048]. By broadest reasonable interpretation, any container reads on a packaging material. The composition taught by Nakajima is a liquid and would require to be in vial or container to hold the liquid. As set forth above, the teachings of Nakajima, Kulvik, Waterman, and Gustafsson would result in a composition comprising p-boronophenylalanine, sorbitol, and sulfite, wherein the pH is in the range of 6.5 to 7.5, in a sealed infusion bag for injection, which reads on a packaging material as defined by the instant specification.
Applicant argues:
Table 2 of the present application shows that, when an inert gas atmosphere (e.g., nitrogen bubbling) is not applied during the filling step and the heat sterilization step is not performed, the dissolved oxygen concentration of the liquid composition is 4 ppm or more, which is outside the claimed range of the dissolved oxygen concentration of claim Conditions I and II. In contrast, when an inert gas atmosphere (e.g., nitrogen bubbling) is applied during the filling step and the heat sterilization step is performed, the dissolved oxygen concentration of the liquid composition satisfies claim Conditions I or II in all instances.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., inert gas atmosphere (e.g., nitrogen bubbling) applied during the filling step and the heat sterilization are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Moreover, the claims do not require the packaging material listed in Table 1 [0063] just that the composition is packaged in packaging material that is sealed. Thus, the comparison examples are not commensurate in scope with the instant claims. MPEP 716.02(d) states:
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). In the instant case, 4 examples of packaging materials with made of specific materials having specific film thickness and oxygen permeability is not commensurate in scope with the instant claims.
Applicant argues:
Applicant has unexpectedly discovered that controlling the concentration of dissolved oxygen in a liquid composition containing BPA can inhibit changes in the liquid composition and prevent the liquid from becoming colored when the liquid is stored for a long period of time. The claimed pharmaceutical kit, comprising a liquid composition that satisfies claim Condition I
or Condition II, can be obtained by accommodating the liquid composition in a packaging material, and subsequently heat-sterilizing the pharmaceutical kit under an inert gas atmosphere.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., inert gas atmosphere (e.g., nitrogen bubbling) applied during the filling step and the heat sterilization are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Moreover, the claims do not require the packaging material listed in Table 1 [0063] just that the composition is packaged in packaging material that is sealed. Thus, the comparison examples are not commensurate in scope with the instant claims. MPEP 716.02(d) states:
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). In the instant case, 4 examples of packaging materials with made of specific materials having specific film thickness and oxygen permeability is not commensurate in scope with the instant claims.
Moreover, as set forth above, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to utilize the infusion bag container taught by Gustafsson to store the composition taught by Nakajima with an expectation of success, since the prior art establishes that boronophenylalanine is susceptible to oxidation, sulfites are particularly effective antioxidants in systems where amount of oxygen is limited, and the storage containers of Gustafsson are useful for limiting oxygen exposure. It is not unexpected that reducing oxygen exposure of the composition results in less degradation of the composition due to oxidation.
Conclusion
Claims 1-8 are rejected.
No claim is 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 RAYNA B RODRIGUEZ whose telephone number is (571)272-7088. The examiner can normally be reached 8am-5:00pm, Monday - Thursday.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached at 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Rayna Rodriguez/ Primary Examiner, Art Unit 1628
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