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 .
The Applicants’ Amendment to the Claims filed on 01/26/2026 is entered.
Claims 1-5 and 7-10 are pending and under examination.
Priority
This US17/555,375 filed on 12/18/2021 which is a CON of PCT/CN2021/102050 filed on 06/24/2021 claims foreign priority to CHINA 202010595084.3 filed on 06/28/2020. Note that an English language translation of CHINA 202010595084.3 has not been provided.
Response to Amendment
Any/all objections and rejections made in the previous office action and not repeated in this office action are withdrawn in light of the Applicants’ Amendment to the Claims filed on 01/26/2026.
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.
Claims 1-5, and 7-10 are rejected under 35 U.S.C. 103 as being unpatentable over Longo (US Patent 5,134,121, published 07/28/1992; of record), in view of Fisher et al (WO 98/01555 published 01/15/1998; of record), in view of Siekmann et al (US2012/0035344 published 02/09/2012; of record), in view of either of Ohtsuka (EP 329175 published 08/23/1989; of record) and Chen et al (WO2013013626-A1 published January 30, 2013; of record), in view of CN-108265044A to Ma et al (published 07/10/2018, see STIC result 5 of 7, page 19) and CN-108530636A to Weng et al (“Monofunctional branched polyethylene glycol suitable for drug modification”; published 09/14/2018; IDS ref; see attached STIC result 4 of 7, page 13; IDS ref)
Regarding claims 1-5, and 7-10, Longo teaches that recombinant human nerve growth factor called rhNGF is well-known in the art for use as a therapeutic agent and that NGF is a dimer formed by two identical 118 amino acid chains. (See col 6, lines 48-68; col 17: “General Methods of Use”.) Longo disclose recombinant human NGF. (See col 6, lines 48-68.) Longo discloses that administration of NGF may be in combination with a pharmaceutically acceptable excipient, including PEG. (See col 18, line 2.) Also, Longo discloses that one may incorporate the NGF peptides in a suitable polymer matrix, thus providing a sustained-release delivery device. (See col 18, lines 9-13.)
In addition, Fisher et al (1998) teach a method for preparing a modified protein of interest, comprising reacting the PEG polymer with a recombinant protein of interest. Fisher et al teach that the size of water soluble polymers attached to proteins of interest may have an effect on the therapeutic profile of such, including “the duration of the sustained release; the effects on biological activity; the ease of handling; the degree or lack of antigenicity” (See page 33, lines 17-22). Fisher et al teach attaching water soluble polymers to the sTNFRs for preparation of a therapeutic product. (See page 32, lines 3-19). Fisher et al teach that polyethylene glycol (PEG) is a “clinically acceptable water soluble polymer”. (See page 32, lines 17-19). Fisher et al disclose that PEG is “intended to encompass any of the forms that have been used to derivative other proteins, such as mono-(C1-C10) alkoxy- or aryloxy-PEG. Fisher et al teach that the water soluble polymers have an average molecular weight of between about 3kDa to about 100kDa. Preferred embodiments are between about 5kDa and about 50kDa and most preferred being between about 20kDa and about 35kDa.. (See page 33, lines 1-14).
Regarding claims 1 and 3-5, each of Siekmann et al and Longo disclose therapeutic NGF polypeptide conjugated to polyethylene glycol (PEG). Siekmann et al disclose that it was well-known in the art to attach a PEG to the alpha-amino terminus of a therapeutic polypeptide. Siekmann et al discloses PEGylation of NGF polypeptide in Example 36. (see pages 172-175). In para 00144, Sieckmann et al reports that the PEGylated therapeutic protein was functional and also had an extended half-life in vivo. Siekmann et al disclose using linear 20 kD PEGylation reagents.
Regarding claim 2, Longo teaches that recombinant human nerve growth factor called rhNGF is well-known in the art for use as a therapeutic agent and that NGF is a dimer formed by two identical 118 amino acid chains. (See col 6, lines 48-68; col 17: “General Methods of Use”.) Longo discloses that administration of NGF may be in combination with a pharmaceutically acceptable excipient, including PEG. (See col 18, line 2.) Instant SEQ ID NO:1 is a 118 amino acid sequence. Instant SEQ ID NO:2 is a 117 amino acid sequence. Ohtsuka teaches a recombinant human nerve growth factor called rhNGF which has the amino acids of instant SEQ ID NO:1. Chen et al teaches an rhNGF which has the amino acid sequence of instant SEQ ID NO:2. See ABSS results for each of and Chen et al just below.
ABSS RESULT 1 for SEQ ID NO:1
AAP91034
ID AAP91034 standard; protein; 118 AA.
AC AAP91034;
DT 20-JUL-2000 (revised)
DT 14-DEC-1989 (first entry)
DE Human nerve growth factor segment.
KW Human nerve growth factor; fusion protein; thrombin; geriatric dementia; nervous disorders; human growth hormone.
OS Homo sapiens.
CC PN EP329175-A.
CC PD 23-AUG-1989.
CC PF 17-FEB-1989; 89EP-00102795.
PR 19-FEB-1988; 88JP-00035042.
CC PA (TOYJ ) TOSOH CORP.
Ohtsuka E;
DR WPI; 1989-243092/34.
CC PT New human nerve growth factor gene encoding fusion protein - having cleavage site for thrombin, useful for treating geriatric dementia, etc.
CC PS Claim 5; Page 16; 38pp; English.
Human nerve growth factor (hNGF) segment (see AAN90577). The patent describes a fusion protein formed from nerve growth factor and human growth hormone and including a thrombin recognition sequence such that hNGF is released by incubation with thrombin. hNGF controls geriatric dementia and nervous disorders. (Revised entry issued to correct the sequence analysis breakdown.)
Sequence 118 AA;
Query Match 100.0%;Score 642;Length 118;
Best Local Similarity 100.0%; Matches 118; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 SSSHPIFHRGEFSVCDSVSVWVGDKTTATDIKGKEVMVLGEVNINNSVFKQYFFETKCRD 60 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SSSHPIFHRGEFSVCDSVSVWVGDKTTATDIKGKEVMVLGEVNINNSVFKQYFFETKCRD 60
Qy 61 PNPVDSGCRGIDSKHWNSYCTTTHTFVKALTMDGKQAAWRFIRIDTACVCVLSRKAVR 118 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
PNPVDSGCRGIDSKHWNSYCTTTHTFVKALTMDGKQAAWRFIRIDTACVCVLSRKAVR 118
ABSS RESULT 1 For Instant SEQ ID NO:2
BAK16893
ID BAK16893 standard; protein; 117 AA.
AC BAK16893;
DT 11-APR-2013 (first entry)
Human nerve growth factor deletion mutant protein, SEQ:1.
NGF ligand; Nerve growth factor ligand; mutein; protein production; recombinant protein.
OS Homo sapiens.
CC PN WO2013013626-A1.
CC PD 31-JAN-2013.
CC PF 26-JUL-2012; 2012WO-CN079188.
PR 28-JUL-2011; 2011CN-10213670.
(CHPL-) CHINA PLA MILITARY MEDICAL SCI ACAD BIOT.
Chen W, Fang T, Fu L, Hou L, Song X, Yu R, Yu T;
DR WPI; 2013-B68280/11.
New deletion mutant of recombinant human nerve growth factor used in expression vector for transforming host cell, comprises peptide chain of complete human nerve growth factor with specific amino acid deleted.
CC PS Claim 1; SEQ ID NO 1; 23pp; English.
CC The present invention relates to a novel deletion mutant of recombinant human nerve growth factor which is used in an expression vector for transforming a host cell. The deletion mutant of recombinant human nerve growth factor comprises a polypeptide chain of complete human nerve growth factor with specific amino acid deleted. The invention independently claims: (a) a gene encoding the deletion mutant of recombinant human nerve growth factor; (b) a method for preparing the gene; (c) expression vector comprising the gene; (d) a method for expressing the vector; and (e) the host cell containing the expression vector. The present sequence represents a human nerve growth factor deletion mutant protein which is used in the expression vector for transforming the host cell.
SQ Sequence 117 AA;
Query Match 100.0%; Score 637; Length 117;
Best Local Similarity 100.0%; Matches 117; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 SSSHPIFHRGEFSVCDSVSVWVGDKTTATDIKGKEVMVLGEVNINNSVFKQYFFETKCRD 60 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
SSSHPIFHRGEFSVCDSVSVWVGDKTTATDIKGKEVMVLGEVNINNSVFKQYFFETKCRD 60
PNPVDSGCRGIDSKHWNSYCTTTHTFVKALTMDGKQAAWRFIRIDTACVCVLSRKAV 117 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
PNPVDSGCRGIDSKHWNSYCTTTHTFVKALTMDGKQAAWRFIRIDTACVCVLSRKAV 117
In view of the high skill level in the art, it is considered that one of ordinary skill in the art would have been motivated to use the human NGF of instant SEQ ID NOs disclosed in Chen et al and Ohtsuka for the rationale of making a therapeutic protein for treating a nervous disorder condition. It would have been prima facie obvious to use either of these versions of hNGF because Chen et al and Ohtsuka disclose that these hNGF sequences were used for therapeutic hNGF. It is considered that one of ordinary skill in the art would have had a reasonable expectation of success to use these hNGF sequences to arrive at the presently claimed invention.
In addition, regarding claims 7-10, Longo and Siekmann et al do not recite the specific elements of PEGylation.
Regarding claim 7-8, Fisher et al teaches a method for preparing a modified protein of interest, comprising reacting the PEG (polymer of formula A in claim 4) with a recombinant protein of interest. Fisher et al teach attaching water soluble polymers to the sTNFRs for preparation of a therapeutic product. (See page para 0331). Fisher et al teach that polyethylene glycol (PEG) is a “clinically acceptable water soluble polymer”. (See para 0088). Fisher et al disclose that PEG is “intended to encompass any of the forms that have been used to derivative other proteins, such as mono-(C1-C10) alkoxy- or aryloxy-PEG. Fisher et al teach that the water soluble polymers have an average molecular weight of between about 3kDa to about 100kDa. Preferred embodiments are between about 5kDa and about 50kda and most preferred being between about 20kDa and about 35kDa.. (See para 0089-0090).
Fisher et al teach that attachment of the PEG to the protein of interest is obtained by covalent binding of the PEG and an N-terminal α-amino group of the recombinant protein. (See para 0329-0332). Fisher et al teaches that the reaction takes place in the presence of sodium cyanoborohydride serving as a preferred type of reducing agent.(See para 0329-0332). Fisher et al teach that the reducing agent, sodium cyanoborohydride, has a final concentration of 20 mM. (See para 0331.)
Fisher et al teaches the polymer of formula A (PEG) and the recombinant protein of interest are in a molar ratio of “1:1 to 100:1” which meets the limitation of 1-2:1. (See para 331.)
Regarding claim 9, Fisher et al teaches that reaction solvent is acetic acid/sodium acetate buffer solution, and a resulting reaction system has a pH value of 5.0-5.8. (See para 329-332.)
Regarding claim 10, Fisher et al teaches that a reaction temperature is 5±30C or 25±20C and a reaction time is in the range of 2 h to 24 h. (See para 329-332.)
Ma et al (CN-108265044A) discloses a polyethylene glycol-modified ADI and preparation of such. Ma et al discloses that the polyethylene glycol (PEG) site-directed modified arginine deiminase (ADI) has structural general formula shown attached STIC result 5 of 7, page 19 and just below, and ref claim 4). Ma et al disclose the N-disubstituted structure with two PEGs on the same nitrogen. See attached STIC result 5 of 7, page 19 and just below, ref claim 4).
PNG
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308
374
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Greyscale
Further, Ma et al disclose a pharmaceutical composition containing the PEG-modified ADI, where the molecular weight of the PEG, such as Y-PALD-40K, is 30-40 kDa, the reducing agent is sodium cyanoborohydride, the buffer is acetic acid-sodium acetate, the pH value is 5.0, the reaction temperature is 4 degrees C, and the reaction time is 18 h (see ref claims 110, abstract, para 1116-1128, and 0042-0150). Ma et al discloses preparation by adding ADI in acetic acid-sodium acetate buffer solution, adding PEG and reducing agent, reacting at 4-20°C for 12-24 h, and performing ion exchange chromatography purification wherein the PEG is coupled on the N-terminal amino of one or two subunits of ADI, is branching type, and the mol. wt. thereof is 30-40 kDa. Also, Ma et al discloses a drug compound containing PEG site-directed modified ADI or pharmaceutically acceptable salt or complex thereof, and adjuvant, and application of the PEG site-directed modified ADI or pharmaceutically acceptable salt or complex thereof in preparation of a drug for treating arginine-deficient tumor disease. Ma et al disclose that their inventive PEG modified ADI has high stability and activity, and low immunogenicity, and is suitable for industrial production.
In addition, Weng et al teach monofunctional branched polyethylene glycol suitable for drug modification comprising the N-disubstituted formula of the present claims. (See title, abstract, see attached STIC result 4 of 7, page 13).
The level of skill in the art was high before the effective filing date of the presently claimed invention.
One of ordinary skill in the art would have been motivated to use the methods of Fisher et al, Ma et al and Weng et al to conjugate PEG to a therapeutic NGF protein, for the rationale of making a therapeutic protein with prolonged half-life and improved biological activity. Fisher et al teach that the reaction should avoid conditions such as temperature, solvent, and pH that would inactivate the protein to be modified. Further, Ma et al disclose that their PEG modified ADI has high stability and activity, and low immunogenicity, and is suitable for industrial production.
It would have been obvious for one of ordinary skill in the art to do such because Fisher et al teach that water soluble polymers (PEG) attached to proteins of interest may have an effect on the therapeutic profile of such, including the duration of the sustained release; the effects on biological activity; the ease of handling; the degree or lack of antigenicity. Ma et al disclose that their PEG modified ADI has high stability and activity, and low immunogenicity, and is suitable for industrial production.
In view of the high skill level in the art before the effective filing date of the presently claimed invention it is considered that one of ordinary skill in the art would have had a reasonable expectation of success to combine the elements of the cited references to arrive at the presently claimed invention.
Response to Arguments
The Applicants’ arguments filed on January 26, 2026 has been fully considered but is unpersuasive. The applicants argue that “a polymer of Formula A contains an N-disubstituted amino acetamino aldehyde derivatized with two PEG on the nitrogen atom”.
The applicants argue:
Longo does not disclose covalent PEGylation of NGF, nor does it suggest modifying NGF using branched PEG aldehydes or any aldehyde-mediated chemistry. Longo discloses PEG only as an excipient component in compositions containing NGF. In addition, Longo teaches that NGF peptides may be incorporated into a polymer matrix to provide a sustained-release delivery device. In both cases, PEG and NGF are merely physically mixed or non-covalently associated, and PEG functions as a carrier or formulation aid rather than as a covalently attached modifier. These teachings are fundamentally different from the claimed invention, which requires a uniform covalent conjugate formed by linking a specific PEG aldehyde derivative to the N- terminal α-amine of recombinant human NGF.
However, this argument is unpersuasive because Fisher et al teach covalent PEGylation of protein of interest. The present rejection is not for anticipation but rather is for obviousness over a combination of references under 35 U.S.C. 103. Fisher et al teach that attachment of the PEG to the protein of interest is obtained by covalent binding of the PEG and an N-terminal α-amino group of the recombinant protein. (See para 0329-0332). Fisher et al teaches that the reaction takes place in the presence of sodium cyanoborohydride serving as a preferred type of reducing agent.(See para 0329-0332). Fisher et al teach that the reducing agent, sodium cyanoborohydride, has a final concentration of 20 mM. (See para 0331.)
Also, the applicants argue that
Fisher et al teaches PEGylation of a different target protein under materially different conditions. Fisher et al. describes PEGylation of soluble TNF receptors (sTNFRs) to prepare therapeutic products, not PEGylation of NGF. As set forth in Examples C (PEGylation), Fisher employs: mono-t-butoxy polyethylene glycol in Examples 1 and 2, at PEG:protein molar ratios of 3:1 or 2:1, under acidic conditions (pH 4.0 or 5.0); and mono-methoxy polyethylene glycol aldehydes in Examples 3 and 4, under 10 mM sodium phosphate buffer at pH 6.5. Thus, Fisher's target protein (sTNFRs), PEG structures, PEG stoichiometry (≥2 equivalents) differ materially from those of the claimed invention. Such conditions are tailored to sTNFRs, which are structurally and functionally distinct from NGF. Nothing in Fisher suggests that its PEGylation strategies would be applicable to NGF.
However,
However, this argument is unpersuasive because the present rejection is not for anticipation but rather is for obviousness over a combination of references under 35 U.S.C. 103. Longo teaches that recombinant human nerve growth factor called rhNGF is well-known in the art for use as a therapeutic agent and that NGF is a dimer formed by two identical 118 amino acid chains. (See col 6, lines 48-68; col 17: “General Methods of Use”.) Longo discloses that administration of NGF may be in combination with a pharmaceutically acceptable excipient, including PEG. (See col 18, line 2.) Siekmann et al disclose that it was well-known in the art to attach a PEG to the alpha-amino terminus of a therapeutic polypeptide. Siekmann et al discloses PEGylation of NGF polypeptide in Example 36. (see pages 172-175). In para 00144, Sieckmann et al reports that the PEGylated therapeutic protein was functional and also had an extended half-life in vivo. Siekmann et al disclose using linear 20 kD PEGylation reagents.
Further, the applicants argue that “Siekmann only discloses that PEG can be attached to alpha-amino terminus of a therapeutic polypeptide, but it failed to disclose the N-disubstituted structure with two PEGs on the same nitrogen.
However, this argument is unpersuasive because the present rejection is not for anticipation but rather is for obviousness over a combination of references under 35 U.S.C. 103. Specifically, this argument is unpersuasive because each of the references of Weng et al (CN 108530636 A) and CN 108265044 A disclose an N-disubstitution of two PEG segments.
Also, the applicants argue that “Siekmann does not disclose or suggest the elaborate structure of Formula A of the instant claims because it does not disclose the very end structure of Formular A where the two PEGs are attached”.
However, this argument is unpersuasive because each of the references of Weng et al (CN-108530636A) and Ma et al CN-108265044A disclose an N-disubstitution of two PEG segments.
Further, the applicants argue that
Ma et al. discloses PEGylation of arginine deiminase (ADI), a large enzymatic protein, using branched PEG aldehydes that form amide (-CO-NH-) linkages between PEG and the protein backbone. As explained by the inventor, ADI differs fundamentally from NGF in structure, size, folding constraints, and functional sensitivity.
NGF is a small, cysteine-rich neurotrophin whose biological activity depends on precise tertiary structure and receptor-binding surfaces. In contrast, ADI is an enzyme designed to tolerate extensive surface modification for immunogenicity masking. A person of ordinary skill in the art would not reasonably expect that PEGylation strategies developed for ADI -- particularly those involving high PEG loading ratios (4-10:1) and resulting heterogeneous conjugates -- could be successfully transferred to NGF without compromising activity. Crucially, Ma et al. contains no teaching or suggestion that its branched PEG aldehyde chemistry is suitable for NGF, neurotrophins, or similarly delicate growth factors. Nor does Ma provide guidance on selective modification of the N-terminal α-amine of NGF, which is a critical feature of the claimed invention.
Weng is directed to a broadly defined class of monofunctional branched PEG reagents, characterized by an expansive Markush structure encompassing numerous independent variables, including PEG arm identity and length, branching architecture, multiple alternative linker groups, optional connecting units, and a wide array of terminal functional groups. As shown throughout Weng's claims and figures, the number of possible structural permutations is vast, and no particular species is identified as preferred for protein modification, let alone for modification of nerve growth factor (NGF). Importantly, Weng does not disclose any example of modifying NGF, any neurotrophin, or any small, disulfide-rich growth factor. Nor does Weng provide guidance directing a person of ordinary skill in the art to select a specific branched PEG aldehyde structure from among the myriad disclosed possibilities for use with NGF. The Examiner's rejection therefore relies on an impermissible hindsight selection of a particular structure from a large genus, informed only by Applicant's disclosure. In the absence of any teaching in Weng that singles out the claimed structural features as suitable for NGF modification, a person of ordinary skill in the art would have had no reason to select such a structure, and no reasonable expectation that such a selection would successfully yield a biologically functional NGF conjugate.
When Ma is viewed together with Weng, the uncertainty is compounded rather than reduced. Ma teaches high-stoichiometry PEGylation of an unrelated enzyme, while Weng dramatically expands the universe of possible PEG structures without identifying which, if any, would be suitable for sensitive proteins such as NGF. The combination of these references therefore provides even less predictability than either reference alone. The Examiner's rationale effectively assumes that because branched PEG aldehydes exist (Ma/Weng) and PEGylation of NGF exists (Longo/Fisher/Siekmann), a POSITA would combine them. This reasoning is outcome-driven and impermissibly relies on hindsight. Absent Applicant's disclosure, there is no teaching in the art explaining why a POSITA would select branched, N-disubstituted PEG aldehydes for NGF, or why such modification would be expected to succeed given NGF's structural sensitivity. The cited references do not supply the required reasoned motivation with a reasonable expectation of success.
However, this argument is unpersuasive because each of the references of Weng et al (CN-108530636A) and Ma et al CN-108265044A disclose an N-disubstitution of two PEG segments. Fisher et al teaches a method for preparing a modified protein of interest, comprising reacting the water soluble polymer PEG with a recombinant protein of interest. Fisher et al teach attaching water soluble polymers to the sTNFRs for preparation of a therapeutic product. (See page para 0331). Fisher et al teach that polyethylene glycol (PEG) is a “clinically acceptable water soluble polymer”. (See para 0088). Fisher et al disclose that PEG is “intended to encompass any of the forms that have been used to derivative other proteins, such as mono-(C1-C10) alkoxy- or aryloxy-PEG. Fisher et al teach that attachment of the PEG to the protein of interest is obtained by covalent binding of the PEG and an N-terminal α-amino group of the recombinant protein. (See para 0329-0332). Fisher et al teaches that the reaction takes place in the presence of sodium cyanoborohydride serving as a preferred type of reducing agent.(See para 0329-0332). Fisher et al teach that the reducing agent, sodium cyanoborohydride, has a final concentration of 20 mM. (See para 0331.)
Further, it is noted that claim 1 is drawn to a product and not a process. The claim is drawn to a modified recombinant human growth factor. The product-by-process language “obtained from” is generally not afforded patented weight for purpose of applying prior art.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Conclusion
No claim is allowed.
Related prior art which may be applied in a future office action if appropriate:
Dingels et al “Squaric Acid Mediated Chemoselective PEGylation of Proteins: Reactivity of Single-Step-Activated alpha-Amino Poly(ethylene glycol)s” (Chemistry 2012).
Ardiuni et al “Expression, purification, and characterization of rat interferon-beta, and preparation of an N-terminally PEGylated form with improved pharmacokinetic parameters” (Protein Expression & Purification, 2004, Vol 34, pages 229-242).
Weng et al, CN 108530637A (Xiamen Sinopeg Biotechnology, “Method for preparing monofunctionalized branched polyethylene glycol for drug modification” ; published 03/05/2017; STIC 3 of 7, page 9; of record). Weng et al discloses the formula having the disubstituted nitrogen of the instant claims. (See attached STIC structure results).
Buthe et al (US2018/0127686 published 05/10/2018; of record). Buthe et al teach PEGylation of a protein by attachment of one or more PEG moieties by a linker at one or more amino acids. Buthe et al recite:
[0081] The term “PEGylation” as used herein denotes modification of a protein by attachment of one or more PEG moieties via a linker at one or more amino acids. The polyoxyethylene (PEG) moiety is illustratively attached by nucleophilic substitution (acylation) on N-terminal α-amino groups or on lysine residue(s) on the gamma-positions, e.g., with PEG-succinimidyl esters. Optionally, polyoxyethylene moieties are attached by reductive alkylation - also on amino groups present in the protein using PEG-aldehyde reagents and a reducing agent, such as sodium cyanoborohydride.
Fisher et al (USPGPub2005/0250696; of record).
Conclusion
THIS ACTION IS MADE FINAL. 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 CATHERINE S HIBBERT whose telephone number is (571)270-3053. The examiner can normally be reached M-F 8:00-5:00.
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/CATHERINE S HIBBERT/Primary Examiner, Art Unit 1658
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