DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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.
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 November 25, 2025 has been entered.
The amendment filed November 25, 2025 has been entered. Claims 1, 7-9, 13 have been amended. Claim 4 remains withdrawn due to being drawn to a non-elected invention.
Applicant’s arguments filed November 25, 2025 were fully considered but they were not persuasive. Rejections and response to arguments are addressed below.
Claims 1-15 are pending in this application.
Priority
This application is a national stage filing under 35 U.S.C. § 371 of PCT Application No. PCT/JP2019/027455, filed on July 11, 2019, which claims priority of Japanese Application No. 2018-131529, filed on July 11, 2018. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been received
Election
Applicant’s election of the polymer of formula 4 and a peptide/protein drug of claim 6 in the reply filed on April 10, 2024 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant elected the polymer of formula 4 as shown on page 15 of the instant specification that has the following formula:
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(Chem. 4). The elected species was not taught or suggested by the prior art. The search was extended to include additional species of polymers of formula (4) comprising four arginine residues (basic peptide of chain length of 4, wherein the basic peptide is arginine) as was previously encompassed by instant claim 1. The amendment entered November 25, 2025 removed a polymer comprising four arginine residues from the claims, thus the search was extended to include additional species of polymers of formula (4) comprising five or six arginine residues
Applicant has indicated in the remarks that the elected species would encompass claims 1-6. The Examiner notes that claim 4 is limited to a polymer wherein the basic peptide is consisting of arginine and glycine. Formula 4 does not comprise or allow for the incorporation of any glycine molecules. Thus, claim 4 is not encompassed by the elected species and is withdrawn due to being drawn to a non-elected invention.
Additionally in order to facilitate compact prosecution, upon the discovery of additional species that were found in the prior art that read on the present claims, the search was expanded to include the following species:
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wherein R is 6-10.
With respect to the newly added claims, the search was expanded to include additional species:
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wherein R is 6-10;
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wherein the main chain can be hyaluronic acid (as shown) carboxymethylated cellulose or carboxymethylated β-glucose, b is 0 and X2 excludes a terminal amino group and a terminal carboxyl group from a membrane-permeable peptide, wherein the membrane permeable peptide is KLTRAQRRAAARKNKRNTR (ending in 1 arginine), X 3 represents an amino group,
Claims 1-3 and 5-15 are examined herein
Claim Interpretation
According to the instant specification, the term “end of the side chain” means a terminal part of a branched chain which branches off from the main chain and does not re-bond to the main chain (pg. 8, para. 0020). The specification continues, “The side chain containing one arginine at the end thereof…. can contain any chain on the main chain side of one arginine. The any chain is not particularly limited, but, for example, includes a linker peptide” (pg. 8, para. 0020). Thus the broadest reasonable interpretation of the claim includes a peptide than ends in an arginine residue (For example: LLLLLLLLLLLLLLLR).
The phrase “side chain” as recited by instant claim 1 and 7 are interpreted to mean a group that branches off from the polymer backbone (arrow):
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.
The phrase “main chain” as recited by instant claim 2 is interpreted to refer to the polymer backbone (arrow):
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With respect to instant claims 5, 11, and 14 which are directed to an agent and recites the phrase ““for promoting introduction of compound into cells”. The Examiner notes that it is well settled that “intended use” of a composition or product, e.g., “for promoting introduction”, will not further limit claims drawn to a composition, so long as the prior art discloses the same composition comprising the same ingredients (See MPEP 2111.02 (II)). To satisfy an intended use limitation which is limiting, a prior art structure which is capable of performing the intended use as recited in the preamble meets the claim. According to the instant specification, “The agent for promoting introduction of compound of the present invention comprises the polymer compound of the present invention” (pg. 10, para. 0024). The broadest reasonable interpretation of the claimed agent is just the polymer itself.
Claim Objections
Claims 1 and 7 are objected to because of the following informalities:
In claims 1 and 7 the claims use both the letter “R” and the term “arginine” to refer to arginine. The claim should be clarified such that “R” is defined to also refer to arginine, as inclusion of both presents confusion whether R is merely a variable for basic peptides.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 (b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3 and 10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 3: Claim 3 recites inter alia, “….wherein an end of the one arginine….”. There is a lack of antecedent basis for the phrase “the one arginine” in the claim. Thus, claim 3 is rendered indefinite.
Regarding claim 10: Claim 10, which depends from claim 7, recites inter alia, “….wherein an end of the 1 or 2 arginine is -CONH2”. The claim is rendered indefinite because it is unclear whether the claim is referring to solely basic peptides with 1 or 2 arginines, a combination of arginine and glycine, or the arginines that are present at the end of a chain. For example, an arginine at the end of a six arginine length basic peptide comprising 1 arginine ending in -CONH2. The multiple interpretations of the phrase renders the claim indefinite. For examination purposes, the claim will be interpreted such that the end of the basic peptide is -CONH2 group, similar to instant claim 3.
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 13 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 further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claim 13: Claim 13, which depends from claim 7, recites wherein the end comprises 1 arginine. However, claim 7 necessarily requires that the end comprise at least one arginine. Thus, claim 13 fails to further limit claim 7.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-3, 5-8, and 10-15 are rejected under 35 U.S.C. 103 as being unpatentable over Sakuma et al (J. Controlled Release, 2010, cited in previous action) in view of Futaki et al (Bioconjugate Chem., 2001, cited in previous action).
Regarding claims 1-3, 5-8, and 10-15: Sakuma teaches oligoarginines, which are known as cell-penetrating peptides, enhance the cellular uptake of poorly membrane-permeable bioactive molecules that are chemically conjugated to them (abstract). Sakuma teaches the use of a polymer referred to as oligoarginine-linked PNVA-co-AA with the following structure:
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(pg. 190, col. 1, section 3.1, scheme 1), wherein oligoarginine is D-octaarginine (abstract). The polymer comprises polyacrylic acid and polyN-vinylacetamide, which are hydrophilic polymers as defined on pages 6-7 of the instant specification (para. 0016), meeting the limitations of instant claim 2. Sakuma teaches the synthesis of PNVA-co-AA using octaarginine (L- and D-configurations) with amidated terminal carboxyl groups (pg. 188, col. 2, para. 3) The synthesis does not include a step or reactions conditions that would remove the amide at the terminal carboxyl group (pg. 188, col. 2, paras. 5-7). This implies that the structure disclosed in Sakuma contains the terminal amide group as required in claims 3 and 10, or that any modification in the length of the arginine sidechain would also contain this terminal amide group. The molecular weight of these polymers can be greater than 1000 MW, the amount of oligoarginine units can range from 1.4-17.4, and oligoarginine weight can range from 19-78% (pg. 189, table 1). Specifically looking at run 2 of table 1 (pg. 189, table 1), teaches a polymer comprising 1.4 oligoarginine units (i.e. 1), comprising 19% by weight oligoarginine of a 2.6 g/mmol (kDa) polymer, has approximately 0.25mmol/g guanidino residues (one octaaarginine, 2.6g/mmol x 0.19= 0.49 g/mmol octaarginine x 8 arginine (8 guanidines) residues = 3.9g/mmol guanidino =0.25 mmol/g). Sakuma teaches the polymer is a penetration enhancer to enhance the absorption of antidiabetic peptide drugs (i.e. an agent, and pharmaceutical composition comprising a peptide drug, abstract, pg. 188, col. 2, para. 2, pg. 190, col. 2, section 3.2.1, pg. 191, table 2), meeting the limitations of instant claims 5-6, 11-12, and 14-15.
Sakuma does not teach a polymer wherein the basic peptide comprises arginine at a chain length of 5 (RRRRR) or 6 (RRRRRR) as claimed. Sakuma does not explicitly teach a polymer comprising guanidino groups originating from arginine of 0.5 to 20mmol/g.
However, Sakuma teaches that larger amounts of arginine residues can interfere with its synthesis and cites Futaki teaches oligoarginine length can affect internalization efficiency, with lower amount of arginine residues being preferred (pg. 193, col. 2, para. 1, pg. 194, col. 1, para. 1). Futaki teaches membrane permeable arginine-rich peptides and their corresponding membrane permeability (abstract). Futaki demonstrates that octaarginine oligoarginines are the preferred length for internalization efficiency, but also teaches tetraarginine (4 arginine units) oligoarginines are also capable of serving this purpose (pg. 1008, figure 5). Whereas oligoarginines with four units and eight units are known in the art to transport across membranes, it is prima facie obvious to substitute equivalents known for the same purpose (See MPEP 2144.06 (II)). Whereas oligoarginines as low as four and as high as eight are both known to have internalization efficiency, it would have been prima facie obvious to select and arginine length within these two values with a reasonable expectation of success, as the art establishes both are viable options and arginine length directly effects internalization efficiency. Where 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 (See MPEP 2144.05 (II)). Additionally, the Examiner notes a known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use (See MPEP 2123 (II)).
Taken together it would have been prima facie obvious to one of ordinary skill in the art to modify the polymer of Sakuma such that the octaarginine is replaced with a penta- or hexa-arginine (5-6 arginines) as taught by Futaki. A person of ordinary skill in the art would have had the motivation to do so as Sakuma suggests the internalization efficiency is proportional to oligoarginine length, and Futaki demonstrates that both octaarginine and tetraarginines are capable of transporting across membranes. A person of ordinary skill in the art would have had a reasonable expectation of success given that arginine’s of these lengths retain their ability to transport across membranes, which serves the same purpose of the octaarginine unit of Sakuma. Utilizing the calculation of Sakuma discussed above, the polymer rendered obvious would comprise approximately 0.5 mmol/g guanidino residues (one tetraarginine, 2.6g/mmol (kDa, i.e. >1000 MW) x 0.19= 0.49 g/mmol tetraarginine x 5 arginine (5 guanidines) residues = 2.45 g/mmol guanidino = approximately 0.5 mmol/g guanidino groups). The Examiner notes that the MW provided by Sakuma utilized in this calculation does not account for the increased weight due to oligoarginine grafting, thus the mmol/g would further increase. Additionally, wherein Sakuma demonstrates the amount of grafted oligoarginines can vary widely in the polymer, and where 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 (See MPEP 2144.05 (II)).
Claims 1-3 and 5-15 are rejected under 35 U.S.C. 103 as being unpatentable over Sakuma (WO 2016/136707, IDS filed January 8, 2021) in view of Futaki et al (Bioconjugate Chem., 2001, cited in previous action). The English translation relied upon has been provided by the Examiner in a previous action.
Regarding claims 1-3, 5-8, and 10-15: Sakuma teaches the following polysaccharide derivative:
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wherein the main chain is hyaluronic acid, b is 0, X1 represents an octaarginine residue with terminal amino group and a terminal carboxyl group removed, and X3 represents an amino group (English translation, pg. 10, production example 1, pg. 7, structural formula 3). The average molecular weight is 5,000 to 50 million and the d/(c+d) is 0.002 to 1 (English Translation, pg. 7, para. 2). In a specific embodiment the ratio of d/(c+d) is 0.29 and the weight was 220,000 (pg. 10, production example 1). Sakuma teaches using the polysaccharide derivatives as an introduction agent for introducing a low membrane-permeable compound in to cells, such as insulin (English Translation, pg. 8, para. 3). Sakuma teaches alternative membrane permeable peptides can be utilized instead of oligoarginine (English translation, pg. 5, second to last para.). Sakuma teaches the arginine oligomers are preferable 7 to 20 in length (English translation, pg. 5, second to last para.).
Sakuma does not teach a polymer wherein the basic peptide comprises arginine at a chain length of 5 (RRRRR) or 6 (RRRRRR) as claimed.
Sakuma does not explicitly teach wherein said end has one arginine or wherein said polymer comprises a guanidino group originating from arginine of 0.5 to 20 mmol/g as claimed.
However, Futaki teaches membrane permeable arginine-rich peptides and their corresponding membrane permeability (abstract). Futaki demonstrates that octaarginine oligoarginines are the preferred length for internalization efficiency, but also teaches tetraarginine (4 arginine units) oligoarginines are also capable of serving this purpose (pg. 1008, figure 5). Whereas oligoarginines with four units and eight units are known in the art to transport across membranes, it is prima facie obvious to substitute equivalents known for the same purpose (See MPEP 2144.06 (II)). Whereas oligoarginines as low as four and as high as eight are both known to have internalization efficiency, it would have been prima facie obvious to select and arginine length within these two values with a reasonable expectation of success, as the art establishes both are viable options and arginine length directly effects internalization efficiency. Where 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 (See MPEP 2144.05 (II)). Additionally, the Examiner notes a known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use (See MPEP 2123 (II)).
Taken together it would have been prima facie obvious to one of ordinary skill in the art to modify the polymer of Sakuma such that the octaarginine is replaced with a penta- or hexa-arginine (5-6 arginines) as taught by Futaki. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as Sakuma suggests variation in oligoarginine length, and Futaki demonstrates that both octaarginine and tetraarginines are capable of transporting across membranes. A person of ordinary skill would recognize the viability of selecting an arginine length between these values giving the efficiency is dependent on oligoarginine length. Wherein both the peptide and oligoarginines are known in the art to serve this purpose, it is prima facie obvious to substitute equivalents known for the same purpose (See MPEP 2144.06 (II)). Additionally, wherein Sakuma teaches that the ratio of d/(c+d) can be as low as 0.02 and the molecular weight can be 5,000, this equates to a guanidine molar amount of 16.667 mmol/g using the taught peptide (1/(0.002x5g/mmolx6arginine)=16.667 mmol/g). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists (See MPEP 2144.05 (I)).
Regarding claim 9: Sakuma teaches that alternative to hyaluronic acid as the main chain, carboxymethylated polysaccharide derivatives such as modified starch, carboxymethylated cellulose and carboxymethylated β-glucose can be utilized. Wherein the art establishes that the polysaccharides are equivalents, it is prima facie obvious to substitute equivalents known for the same purpose (See MPEP 2144.06 (II)).
Response to Arguments
Applicant’s arguments filed November 25, 2025 have been fully considered but they are not persuasive.
On page 6 of Applicant’s response (last para.), Applicant argues that the newly amended claims exclude tetraarginine, thus the cited references fail to disclose all of the limitations. On page 7 of Applicant’s response (para. 1) Applicant argues that the newly amended claims exclude one arginine, thus the cited references fail to disclose all of the limitations. On page 7 of Applicant’s response (para. 2) Applicant argues that the newly amended claims exclude the known peptide ending in 1 arginine (KLTRAQRRAAARKNKRNITR, of Sakuma II) thus the cited references fail to disclose all of the limitations.
However, see expansion of election to include 5-6 length arginines and see 103 rejections above. Wherein the art establishes arginine lengths ranging from 4-8, it would have been prima facie obvious to select 5 or 6, given that 4 and 8 are tolerable lengths for acting as membrane permeable peptides. Additionally the argument pertaining to China Pharmaceutical rendered moot because the present action does not rely on this reference for any teaching in the art.
Applicant’s reply is considered to be a bona fide attempt at a response and is being accepted as a complete response. The 35 USC § 103 and 112 rejections are maintained for reason of record and foregoing discussion.
Conclusion
No claims are allowed in this action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMUEL L GALSTER whose telephone number is (571)270-0933. The examiner can normally be reached Monday - Friday 8:00 AM - 5:00 PM.
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/S.L.G./Examiner, Art Unit 1693
/ANDREA OLSON/Primary Examiner, Art Unit 1693