A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/10/2025 has been entered.
DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Amendment after Final office action filed on 11/10/2025 is acknowledged.
3. Claims 1-74, 78-80 and 82-99 have been cancelled.
4. New claims 100-105 have been added.
5. Claims 75-77, 81 and 100-105 are pending in this application.
6. Applicant elected without traverse of Group 2 (claims 19-31, 34, 44, 48, 52, 65-67, 69 and 72) and elected with traverse of a pharmaceutical composition comprising about 0.1% (w/v) HGF, wherein the first polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 36 and the second polypeptide comprises or consists of the amino acid sequence of SEQ ID NO: 37; sodium citrate as buffer and pH at about 6.0; about 200 mM trehalose and about 0.05% (w/v) polysorbate 80 (See Example 2, third entry in Table 3) as species of pharmaceutical composition in the reply filed on 3/19/2025. The Examiner telephoned Applicant's representative, Katie E. Hyma, on 3/20/2025 for clarification of the elected species of pharmaceutical composition; and Applicant's representative states on the phone that a pharmaceutical composition comprising about 0.1% (w/v) HGF, wherein the first polypeptide consists of the amino acid sequence of SEQ ID NO: 36 and the second polypeptide consists of the amino acid sequence of SEQ ID NO: 37; 20 mM citrate as buffer and pH at about 6.0; 200 mM trehalose and 0.05% (w/v) polysorbate 80 (the formulation presented as third entry in Table 3 of instant specification) as the elected species of pharmaceutical composition (see PTO-413 dated 3/25/2025).
Restriction requirement was deemed proper and made FINAL in the previous office actions. The instant claims 75-77, 81 and 100-105 are drawn to an aqueous pharmaceutical composition consisting essentially of: about 0.100 (w/v) hepatocyte growth factor (HGF); about 20 mM sodium citrate; about 200 mM of trehalose, and about 0.05%o (w/v) surfactant, in a water-based liquid, wherein the pH of the composition is about 6.0; and an aqueous pharmaceutical composition consisting of: about 0.1% (w/v) hepatocyte growth factor (HGF); about 20 mM sodium citrate; about 200 mM of trehalose, and about 0.05% (w/v) surfactant, in a water-based liquid wherein, the pH of the composition is about 6.0. A search was conducted on the elected species; and prior art was found. Claims 75-77, 81 and 100-105 are examined on the merits in this office action.
Non-compliant Amendment
7. The claim filed on 11/10/2025 is a non-compliant amendment. In the claim filed on 11/10/2025, new claims 100-105 have been added. However, there are changes being made in claims 100 and 105 as indicated by both crossed-out and underlined (see MPEP § 714). Applicant is required to correct this error.
Claim Interpretations
8. With regards to the term “a water-based liquid” recited in instant claims 75 and 101, the instant specification fails to define it. Therefore, for the purpose of this examination and in the broadest reasonable interpretation, the Examiner is interpretating the term “a water-based liquid” broadly includes water and any aqueous solution comprising water and other agents dissolved in it. Such interpretation applies to all the rejections set forth below.
With regards to the term “about” recited in instant claims 75 and 101, the instant specification discloses that “As used herein, the term "about" is used to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 10%.” (see page 26, lines 19-23 of instant specification). Therefore, based on the disclosure of instant specification, for the purpose of this examination, the Examiner is interpretating the term "about" is used to modify a numerical value above and below the stated value by a variance of 10%.
Withdrawn Objections and Rejections
9. Objection to claim 66 is hereby withdrawn in view of Applicant’s amendments to the claim.
10. Rejection to claim 67 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is hereby withdrawn in view of Applicant’s amendment to the claim.
11. Rejection claims 19-22, 27, 29, 31, 65-67, 69, 72 and 99 under 35 U.S.C. 103 as being unpatentable over Chiba (EP 1180368 A1, filed with IDS), and as evidenced by Bottaro et al (Science, 1991, 251, page 802-804, filed with IDS), and in view of Nakamura et al (US 2009/0209463 A1, cited and enclosed in the previous office action) is hereby withdrawn in view of Applicant’s amendment to the claim.
Duplicate Claims Warning
12. Applicant is advised that should claim 77 be found allowable, claim 103 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim (see MPEP § 608.01(m)).
New Objections
13. Claim 75 is objected to for the following minor informality: Applicant is suggested to amend claim 75 as “…about 200 mM trehalose; and about 0.05%o (w/v) surfactant…”.
14. Claim 101 is objected to for the following minor informality: Applicant is suggested to amend claim 101 as “…about 200 mM trehalose; and about 0.05% (w/v) surfactant, in a water-based liquid, wherein the pH…”.
New Rejections
Claim Rejections - 35 U.S.C. § 112 paragraph (b)
15. 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.
16. Claims 75-77, 81, 100 and 103 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 pre-AIA the applicant regards as the invention.
17. Claim 75 recites the term “consisting essentially of”. As stated in MPEP: “The transitional phrase "consisting essentially of" limits the scope of a claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention.” (see MPEP § 2111.03 III). However, in the instant case, the instant specification fails to disclose any materials or steps and those that do not materially affect the basic and novel characteristics of instant claimed aqueous pharmaceutical composition. Therefore, the metes and bounds of instant claim 75 is vague and indefinite. Because claims 76, 77, 81, 100 and 103 depend from indefinite claim 75 and do not clarify the point of confusion, they must also be rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph.
Furthermore, for the purpose of this examination and in the broadest reasonable interpretation, the Examiner is interpretating the term “consisting essentially of” recited in instant claim 75 as “comprising”. Such interpretation applies to all the rejections set forth below.
Maintained/Revised Rejections
Claim Rejections - 35 U.S.C. § 103
18. 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 of this title, 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.
19. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
20. (Revised due to Applicant’s amendment to the claim) Claims 75-77, 81 and 100-105 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Ohori et al (US 2017/0189487 A1, filed with IDS), and as evidenced by Bottaro et al (Science, 1991, 251, page 802-804, filed with IDS), and in view of Nakamura et al (US 2009/0209463 A1, cited and enclosed in the previous office actions).
The instant claims 75-77, 81 and 100-105 are drawn to an aqueous pharmaceutical composition consisting essentially of: about 0.100 (w/v) hepatocyte growth factor (HGF); about 20 mM sodium citrate; about 200 mM of trehalose, and about 0.05%o (w/v) surfactant, in a water-based liquid, wherein the pH of the composition is about 6.0; and an aqueous pharmaceutical composition consisting of: about 0.1% (w/v) hepatocyte growth factor (HGF); about 20 mM sodium citrate; about 200 mM of trehalose, and about 0.05% (w/v) surfactant, in a water-based liquid wherein, the pH of the composition is about 6.0.
Ohori et al, throughout the patent, teach a lyophilized formulation comprising a hepatocyte growth factor (HGF) and trehalose, which is prepared from an aqueous solution comprising HGF, trehalose and a buffer agent; and an aqueous pharmaceutical composition obtained by dissolving the lyophilized formulation, wherein the pH of the aqueous pharmaceutical composition is preferably 5.0 to 6.0, for example, Abstract; page 2, paragraph [0035]; page 4, paragraphs [0070] and [0075]; and page 5, paragraph [0087]. One of such aqueous pharmaceutical compositions in Ohori et al comprises HGF at a concentration of 1.1 mg/ml (equals to 0.11% w/v), trehalose dihydrate at a concentration of 100 mg/ml, citric acid at a concentration of 2.1 mg/ml and polysorbate 80 at a concentration of 0.1 mg/ml (equals to 0.01% w/v) in a water-based liquid, and has a pH of 5.0 to 6.0, such as 5.5 (which is about 6.0), for example, page 5, paragraph [0087]; page 6, Example 8 in Table 2; and page 7, paragraph [0105]. The molecular weight of trehalose dihydrate is 378.33 g/mol, therefore, trehalose dihydrate at a concentration of 100 mg/ml equals to 264 mM. The molecular weight of citric acid is 192.124 g/mol, therefore, citric acid at a concentration of 2.1 mg/ml equals to 10.9 mM. Thus, the aqueous pharmaceutical composition of Example 8 in Ohori et al meets the limitations of the HGF and its concentration, trehalose, the water-based liquid and the pH of the composition recited in instant claims 75 and 101; and polysorbate 80 as a surfactant recited in instant claims 75, 81, 101 and 104. Similar to the aqueous pharmaceutical composition of Example 8 in Ohori et al, Ohori et al further teach various aqueous pharmaceutical compositions that comprise HGF at a concentration of 0.5 mg/ml (equals to 0.05% w/v), 1.0 mg/ml (equals to 0.1% w/v), 1.1 mg/ml (equals to 0.11% w/v), 3.1 mg/ml (equals to 0.31% w/v) or 5.1 mg/ml (equals to 0.51% w/v), trehalose dihydrate at a concentration of 100 mg/ml or 50 mg/ml, citric acid at a concentration of 2.1 mg/ml and polysorbate 80 at a concentration of 0.1 mg/ml (equals to 0.01% w/v) in a water-based liquid, and has a pH of 5.5, for example, page 5, paragraph [0087]; page 6, Examples 12-16 and 18 in Table 3; and page 7, paragraph [0105]. The molecular weight of trehalose dihydrate is 378.33 g/mol, therefore, trehalose dihydrate at a concentration of 50 mg/ml equals to 132 mM. Ohori et al also teach the HGF can be naturally occurred human HGF, for example, page 2, paragraph [0037]. And as evidenced by Bottaro et al, the naturally occurred human HGF is activated HGF and binds to c-MET in epithelial cells (see for example, Title and Abstract). It meets the limitations of instant claims 76 and 102.
The difference between the reference and instant claims 75-77, 81 and 100-105 is that the reference does not explicilty teach a pharmaceutical composition comprising about 0.1% (w/v) HGF, wherein the first polypeptide consists of the amino acid sequence of SEQ ID NO: 36 and the second polypeptide consists of the amino acid sequence of SEQ ID NO: 37; 20 mM citrate as buffer and pH at about 6.0; 200 mM trehalose and 0.05% (w/v) polysorbate 80 (the formulation presented as third entry in Table 3 of instant specification) as the elected species of pharmaceutical composition; sodium citrate and its concentration, and the concentrations of trehalose and surfactant recited in instant claims 75 and 101; and the limitations of instant claims 77, 100, 103 and 105.
However, Ohori et al teach the amount of trehalose in the aqueous pharmaceutical composition comprising HGF is such that the mass ratio between the HGF and trehalose is 1:4 to 1:460, preferably 1:4 to 1:370, and more preferably 1:8 to 1:280, for example, page 3, paragraph [0048]. Ohori et al further teach surfactant is used to prevent reduction of the content of HGF in a drug solution to be administered due to adsorption of the HGF to glass or resin constituting a container after reconstitution of the lyophilized formulation; and the amount of surfactant in an aqueous solution comprising 1.0 mg/mL of HGF is 0.020 to 1.0 mg/mL, preferably 0.050 to 1.0 mg/mL, more preferably 0.075 to 0.5 mg/mL, and still more preferably 0.075 to 0.2 mg/mL, for example, page 5, paragraphs [0078]-[0080]. Ohori et al also teach the buffer in the aqueous pharmaceutical composition comprising HGF can be sodium citrate; and the amount of the buffering agent is between 1 to 100 mM, for example, page 4, paragraphs [0071]-[0073]. Therefore, in view of the teachings of Ohori et al as a whole, one of ordinary skilled in the art would have been motivated to optimize the concentrations of trehalose, sodium citrate as the buffer, and polysorbate 80 as surfactant in the aqueous pharmaceutical composition comprising HGF for improved stability of HGF, including a pharmaceutical composition comprising about 0.1% (w/v) HGF, about 20 mM citrate or sodium citrate as buffer and pH at about 6.0, about 200 mM trehalose and about 0.05% (w/v) polysorbate 80 as a surfactant in a water-based liquid. And, the MPEP states the following: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (see MPEP § 2144.05 II A).
Furthermore, Nakamura et al teach an activated human HGF with the α chain consisting of from the 32nd to the 489th of the amino acid sequence represented by SEQ ID NO: 2 (identical to the amino acid sequence of instant SEQ ID NO: 36), and the β chain consisting of from the 490th to the 723rd of the amino acid sequence represented by SEQ ID NO: 2 (identical to the amino acid sequence of instant SEQ ID NO: 37), for example, page 4, paragraph [0053]; and pages 12-14, SEQ ID NO: 2.
Therefore, it would have been obvious to one of ordinary skilled in the art to combine the teachings of Ohori et al and Nakamura et al with routine optimization to develop an aqueous pharmaceutical composition consisting of about 0.1% (w/v) HGF, wherein the first polypeptide consists of the amino acid sequence of instant SEQ ID NO: 36 and the second polypeptide consists of the amino acid sequence of instant SEQ ID NO: 37; about 20 mM citrate or sodium citrate as buffer and pH at about 6.0; about 200 mM trehalose and about 0.05% (w/v) polysorbate 80 in a water-based liquid, and wherein the composition has a pH of about 6.0. It reads on a pharmaceutical composition comprising about 0.1% (w/v) HGF, wherein the first polypeptide consists of the amino acid sequence of SEQ ID NO: 36 and the second polypeptide consists of the amino acid sequence of SEQ ID NO: 37; 20 mM citrate as buffer and pH at about 6.0; 200 mM trehalose and 0.05% (w/v) polysorbate 80 (the formulation presented as third entry in Table 3 of instant specification) as the elected species of pharmaceutical composition.
One of ordinary skilled in the art would have been motivated to combine the teachings of Ohori et al and Nakamura et al with routine optimization to develop an aqueous pharmaceutical composition consisting of about 0.1% (w/v) HGF, wherein the first polypeptide consists of the amino acid sequence of instant SEQ ID NO: 36 and the second polypeptide consists of the amino acid sequence of instant SEQ ID NO: 37; about 20 mM citrate or sodium citrate as buffer and pH at about 6.0; about 200 mM trehalose and about 0.05% (w/v) polysorbate 80 in a water-based liquid, and wherein the composition has a pH of about 6.0, because Ohori et al teach the amount of trehalose in the aqueous pharmaceutical composition comprising HGF is such that the mass ratio between the HGF and trehalose is 1:4 to 1:460, preferably 1:4 to 1:370, and more preferably 1:8 to 1:280. Ohori et al further teach surfactant is used to prevent reduction of the content of HGF in a drug solution to be administered due to adsorption of the HGF to glass or resin constituting a container after reconstitution of the lyophilized formulation; and the amount of surfactant in an aqueous solution comprising 1.0 mg/mL of HGF is 0.020 to 1.0 mg/mL, preferably 0.050 to 1.0 mg/mL, more preferably 0.075 to 0.5 mg/mL, and still more preferably 0.075 to 0.2 mg/mL. Ohori et al also teach the buffer in the aqueous pharmaceutical composition comprising HGF can be sodium citrate; and the amount of the buffering agent is between 1 to 100 mM. Therefore, in view of the teachings of Ohori et al as a whole, one of ordinary skilled in the art would have been motivated to optimize the concentrations of trehalose, sodium citrate as the buffer, and polysorbate 80 as surfactant in the aqueous pharmaceutical composition comprising HGF for improved stability of HGF, including a pharmaceutical composition comprising about 0.1% (w/v) HGF, about 20 mM citrate or sodium citrate as buffer and pH at about 6.0, about 200 mM trehalose and about 0.05% (w/v) polysorbate 80 as a surfactant in a water-based liquid. And, the MPEP states the following: Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical (see MPEP § 2144.05 II A). Furthermore, Nakamura et al teach an activated human HGF with the α chain consisting of from the 32nd to the 489th of the amino acid sequence represented by SEQ ID NO: 2 (identical to the amino acid sequence of instant SEQ ID NO: 36), and the β chain consisting of from the 490th to the 723rd of the amino acid sequence represented by SEQ ID NO: 2 (identical to the amino acid sequence of instant SEQ ID NO: 37).
A person of ordinary skilled in the art would have reasonable expectation of success in combining the teachings of Ohori et al and Nakamura et al with routine optimization to develop an aqueous pharmaceutical composition consisting of about 0.1% (w/v) HGF, wherein the first polypeptide consists of the amino acid sequence of instant SEQ ID NO: 36 and the second polypeptide consists of the amino acid sequence of instant SEQ ID NO: 37; about 20 mM citrate or sodium citrate as buffer and pH at about 6.0; about 200 mM trehalose and about 0.05% (w/v) polysorbate 80 in a water-based liquid, and wherein the composition has a pH of about 6.0.
Response to Applicant's Arguments
21. Applicant argues that “It would not have been obvious for a skilled artisan to modify the aqueous formulations of Ohori to arrive at the claimed formulations because the formulations of Ohori require an ingredient selected from a specific list of amines that is not in the currently claimed formulations.”; and “One skilled in the art would not have been motivated to remove the required amine ingredient from the formulations of Ohori to arrive at the currently claimed formulations lacking such an ingredient because the amine ingredient of Ohori is said to be necessary for making a lyophilized formulation with improved storage stability.” Applicant further argues that “the present invention represents a stable solution of HGF that does not need lyophilization or additional stabilizing agents to maintain clarity and potency after extended storage in liquid formulation.”
22. Applicant's arguments have been fully considered but have not been found persuasive.
In response to Applicant’s arguments about instant rejection:
First, as stated in Section 8 above, the Examiner is interpretating the term “a water-based liquid” broadly includes water and any aqueous solution comprising water and other agents dissolved in it. Therefore, the rejection set forth in Section 20 above does not require one of ordinary skilled in the art to remove any amine from the aqueous pharmaceutical compositions taught in Ohori et al.
Second, with regards to Applicant’s arguments about that “the present invention represents a stable solution of HGF that does not need lyophilization or additional stabilizing agents to maintain clarity and potency after extended storage in liquid formulation.”, it appears to the Examiner that Applicant is trying to argue about unexpected results. In the instant case, the Examiner would like to point out that as stated in MPEP: “An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness.” (see MPEP § 716.02(e)). In the instant case, the closest prior art is the aqueous pharmaceutical compositions taught in Ohori et al.
Taken all these together, the rejection is deemed proper and is hereby maintained.
Conclusion
No claim is allowed.
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/LI N KOMATSU/Primary Examiner, Art Unit 1658