DETAILED ACTION
Examiner acknowledges receipt of the reply and RCE filed 06/25/2025, in response to the final office action mailed 4/12/2024.
A petition to revive the application was filed on 6/25/2025. The petition to revive was granted on 8/12/2025.
Claims 49-88 are pending. Claim 45-48 have been cancelled. Claims 49, 58-62 and 64-85 remain withdrawn from further prosecution for the reasons previously made of record.
Claims 50-57, 63, and 86-88 are being examined on the merits in this office action.
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 6/25/2025 has been entered.
A notice of abandonment was mailed 5/27/2025. No reply was filed in response to the final office action mailed 4/12/2024.
Applicant filed a petition and fees to revive the application on 6/25/2025. The petition to revive was granted on 8/12/2025.
Claim Objections- withdrawn
The objection of claim 46 is withdrawn in view of the cancellation of the claim in the amendment filed 6/25/2025.
Response to Arguments
Applicant's arguments filed 6/25/2025 have been fully considered but they are not persuasive.
Upon further consideration, a new ground(s) of rejection is made in view of the amendment filed 6/25/2025.
An action on the merits is presented herein.
Specification
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
Maintained Rejection
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
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 pre-AIA 35 U.S.C. 103(a) 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 50-57, 63, and 86-88 remain/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Bossard et al. (WO 2010/033207 A1- previously cited), in view of Shechter et al. (U.S. 2006/0171920 A1- previously cited), as evidenced by Tsuberry et al. (J. Biol. Chem. 279:38118-124 (2004)- previously cited) and Shechter et (Proceedings of the 4th International Peptide Symposium pp. 1-3 (2007))- hereinafter “Shechter 2”)- previously cited). This rejection is maintained from the office action mailed 4/12/2024, but has been amended to reflect claims filed 6/25/2025.
Examiner notes that Shechter is an author of Tsuberry et al. Tsuberry et al. is cited as evidence of the reversible PEGylated drugs method taught in Shechter et al. (Fig. 1 of Tsuberry et al. shows a figure schematic for preparing PEG-FMS-peptide/protein conjugates). Shechter is the author of Shechter 2. The reference is cited as evidence of the advantages of reversible pegylation of proteins over conventional pegylation.
Bossard et al. teach peptides that have been chemically modified by covalent attachment of a water-soluble oligomer (abstract). The peptide conjugates comprise a residue of a therapeutic peptide moiety covalently attached, either directly or through a spacer moiety of one or more atoms, to a water-soluble, non-peptidic polymer (claim 1). The polymer can be PEG (claim 8). Peptides include oxyntomodulin (paras. [0056], [0058]). Para. [0058] teaches 42 exemplary therapeutic peptides, including oxyntomodulin. Example 13 specifically teaches an oxyntomodulin-PEG conjugate. The oxyntomodulin of SEQ ID NO: 248 of Bossard et al. has 100% identity with instant SEQ ID NO: 1. Bossard et al. teach that the linker may be cleavable (e.g., paras. [00130], [00154]-[00155]). Bossard et al. further teach that PEG reagents include hydrolyzable and/or releasable PEGs and linkers (para. [00134]). The therapeutic peptide and the polymer are each covalently attached …, e.g., Fmoc or FMS and are releasable under physiological conditions. Id.
Bossard et al. do not explicitly teach an oxyntomodulin-PEG conjugate comprising moiety of instant claims 50 and 86,
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However, Shechter et al. teach reversible pegylated drugs provided by derivatization of free functional groups of the drug selected from amino, hydroxyl, mercapto, phosphate and/or carboxyl with groups sensitive to mild basic conditions such as 9-fluorenylmethoxycarbonyl (Fmoc) or 2-sulfo-9-fluorenylmethoxycarbonyl (FMS), to which group a PEG moiety is attached (abstract). A preferred embodiment of Shechter et al. is
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wherein R2 is H, or –SO3H (para. [0093]). When R2 is H, a herein designated PEG-Fmoc-drug Y conjugate is obtained (para. [0094]). Y is preferably a peptide or protein drug. When R2 is — SO3H, a PEG-FMS-drug Y conjugate is obtained. Id. Another preferred embodiment is
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wherein R2 is H (Fmoc), or –SO3H (FMS) (paras. [0095]-[0096]). The R2 variable is the same in instant claims 50 and 86. The Y position is the drug residue. Id. The drugs are preferably drugs containing an amino group, most preferably peptides and proteins of low or medium molecular weight (e.g., abstract, paras. [0094], [0127], [0181]).
In these pegylated drugs, the PEG moiety and the drug residue are not linked directly to each other, but rather both residues are linked to different positions of the scaffold Fmoc or FMS structure that is highly sensitive to bases and is removable under physiological conditions (e.g., para. [0181]). Thus, a prodrug is obtained that is inactive, but undergoes transformation into the active drug under the physiological conditions of the body. The prodrug has an extended circulation life but the PEG moiety is removed together with the Fmoc or FMS moiety and the drug recovers its full pharmacological potency. Id. Shechter et al. teach that the combination of the protein-pegylation technology with Fmoc or FMS which are removable under mild basic conditions is able to overcome major deficiencies of the protein-pegylation technology, mainly the loss of biological and pharmacological potencies of the PEG conjugates in vivo (paras. [0015]-[0017], [0181]-[0184]).
This approach enables the desirable pharmacological features associated with pegylation to be conferred on low molecular-weight peptide and protein drugs that would otherwise have been fully or partially inactivated by this technique. Id. The reversible PEG-protein conjugates can be inactive when administered and permit time-dependent reactivation of the inactivated pegylated protein under physiological conditions in the body. Id. A pharmacologically silent conjugate that is trapped in the circulatory system releases the covalently linked parent peptide or protein, with a desirable pharmacokinetic profile. Id. The PEG moieties of the protein-PEG can be released by hydrolysis (cleavable) under physiological conditions in the body. Id. This approach extends the life-time, bioavailability and efficacy of existing peptide drugs. Id.
The FMS or Fmoc group can be reversibly covalently attached to a free amino group of the polypeptide/peptide drug (e.g., paras. [0025], [0083], [0125], claim 122; Fig. 1 of Tsuberry et al. schematic of method). For instance, exendin-4 contains one His Nα amino function and two Lys Nε amino groups, enabling modification at these three positions (para. [0296]). Shechter et al. teach pharmaceutical salts such as hydrochloric acid and acetic acid (para. [0149]). Shechter et al. further teach pharmaceutical compositions comprising the pegylated compound and a pharmaceutically acceptable carrier (para. [0194]). Shechter et al. teach PEG polymers of 5K-40K (e.g., paras. [0003], [0025]).
Shechter 2 states:
PEGylation of therapeutic peptides/proteins creates molecules that exhibit superior pharmacokinetic stability compared to their corresponding unmodified parent molecules. However, this approach [conventional protein pegylation] becomes unproductive if conjugates lose their biological activity upon PEGylation. This major deficiency can be overcome if PEG chains are linked to the peptide/protein drugs through a chemical bond that undergoes slow hydrolysis under physiological conditions.
Reversible Pegylation - Based on our Fmoc/FMS technology we have designed and synthesized two hetero-bifunctional agents of the structures shown in Figure 1. These agents allow the linkage of any peptide or protein containing amino function(s) through a slowly hydrolysable bond. The MAL (3-maleimidopropionic acid)-moiety of this compound allows the attachment of sulfhydryl containing polyethylene glycol (i.e. PEG40-SH, a 40 kDa branched polyethylene glycol containing a sulfhydryl moiety). We have developed the experimental conditions to allow covalent linkage of a single PEG-chain to peptide/protein drugs through either MAL-FMS-OSu (9-hydroxymethyl-2-(amino-3-maleimidopropionate)-7-sulfofluorene N-hydroxysuccinimide;) or MAL-Fmoc-OSu.( 9-hydroxymethyl-2-(amino-3-maleimidopropionate)-fluorene-N-hydroxysuccinimide). A PEG-chain of 40 kDa (PEG40) was used exclusively. The attachment of a single PEG40-chain to any peptide and/or protein was documented two prolong the lifetime of the corresponding conjugates 7-10 times in rodents.
Shechter 2 at p. 1, right column.
The major problem of inactivating short-lived therapeutic peptide and protein drugs by conventional pegylation has been ameliorated, enabling now lifetime extension, bioavailability and efficacy of existing peptide drugs as well as those to be discovered by genomics and proteomics.
Shechter 2 at p. 3, left column. (Emphasis added).
The U.S. Federal Circuit has explicitly stated that in order to make a prima facie case of obviousness, the suggestion and motivation to combine the references need not be explicitly stated in the text of the references. In DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641 (Fed. Cir. 2006), the Court writes, “the suggestion test is not a rigid categorical rule. The motivation need not be found in the references sought to be combined, but may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself. In re Dembiczak, 175 F.3d 994, 999 [50 USPQ2d 1614] (Fed. Cir. 1999). As we explained in Motorola, Inc. v. Interdigital Tech. Corp., 121 F.3d 1461, 1472 [43 USPQ2d 1481] (Fed. Cir. 1997), ‘there is no requirement that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.’” See Dystar at 1645. “Our suggestion test is in actuality quite flexible and not only permits, but requires, consideration of common knowledge and common sense.” See Dystar at 1650. See also In re Fout, 675 F.2d 297, 301 (CCPA 1982).
In view of the combined teachings of Bossard et al., Shechter et al. and Shechter 2, it would have been obvious to the skilled artisan to have prepared an oxyntomodulin-PEG conjugate wherein PEG was attached to the oxyntomodulin via Fmoc or FMS to form a reversible/cleavable PEG conjugate. The skilled artisan would have known of an oxyntomodulin-PEG conjugate from Bossard et al. Example 13 of Bossard reduced to practice OXM-PEG conjugates, including mPEG-MAL. The skilled artisan would have known that Bossard et al taught a oxyntomodulin of SEQ ID NO: 248 which had100% identity with instant SEQ ID NO: 1 (reads on consisting of SEQ ID NO:1). Bossard et al further taught that PEG reagents include hydrolyzable and/or releasable PEGs and linkers (para. [00134]). The therapeutic peptide and the polymer are each covalently attached …, e.g., Fmoc or FMS and are releasable under physiological conditions. Id. The skilled artisan would have been motivated to modify the oxyntomodulin-PEG of Bossard with a reversible-PEG moiety of Shechter et al. because Shechter 2 taught advantages of a reversible PEG moiety over conventional peptide-PEG conjugates, e.g., the loss of biological and pharmacological potencies of the peptide-PEG conjugates in vivo. Shechter et al. and Shechter 2 specifically recognized a need to improve peptide/protein-PEG conjugates through the use of a reversible/cleavable PEG conjugate. The reversible PEG-protein conjugates could be inactive when administered and permit time-dependent reactivation of the inactivated pegylated protein under physiological conditions in the body. The PEG moieties of the protein-PEG could be released by hydrolysis (cleavable) under physiological conditions in a subject. Shechter et al further states that the PEG moiety may be linear or branched PEG and has a molecular weight in the range of 200 to 200,000 Da, preferably up to 80,000 Da, more preferably 5,000-40,000 Da [5 kDa – 40 kDa],and most preferably between about 20,000 Da and 40,000 Da (para. [0190]).
The skilled artisan would have had a reasonable expectation of success in preparing a reversible OXM-PEG conjugate because Shechter et al. taught the reversible PEG moiety components and methods of preparing the conjugates. Shechter et al. specifically taught:
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In this formula, Y is oxyntomodulin of Bossard et al. Shechter et al. taught that preferred cleavable linkers include MAL-Fmoc- and MAL-FMS (e.g., [0099]-[0103]). The PEG moiety could be PEG40 (e.g., 40 kDa, Shechter et al. at paras. [0164], Ex. 13, 15). Bossard expressly taught an OXM sequence consisting of instant SEQ ID NO:1 (SEQ ID NO:248 has 100% identity with SEQ ID NO:1).
Accordingly, the limitations of instant claims 50 and 86 are satisfied. Regarding claims 51-53, these claims are deemed to recite product by process limitations thus the limitations are satisfied by the functional and structural limitations of the oxyntomodulin-PEG conjugates. Regarding claims 54-57, Shechter et al. teach pharmaceutical compositions comprising the pegylated compound and a pharmaceutically acceptable carrier (e.g., abstract; paras. [0099]-[0103], [0164], [0194]). Claim 63 is deemed to recite a functional limitation/property- “prolonged half-life relative to oxyntomodulin". This property is construed as being inherent to the oxyntomodulin-PEG conjugates. Shechter et al. further teach that the reversible PEG moiety prolongs the circulating half-life of the peptide drug (paras. [0004], [0005], [0013]). Regarding claims 87-88, Shechter et al. taught that the PEG moiety could be PEG40 and n=1 (e.g., Shechter et al. at paras. [0164], Ex. 13, 15, 20). The PEG can be branched or linear (e.g., Shechter et al at paras. [0025], [0060], [0190]). Shechter et al states that the PEG moiety may be linear or branched PEG and has a molecular weight in the range of 200 to 200,000 Da, preferably up to 80,000 Da, more preferably 5,000-40,000 Da [5 kDa – 40 kDa],and most preferably between about 20,000 Da and 40,000 Da (para. [0190]). Accordingly, claims 87-88 are deemed to be obvious.
Accordingly, claims 50-57, 63, and 86-88 are rendered obvious in view of Bossard et al., Shechter et al., Tsuberry et al. and Shechter 2.
Response to arguments
Applicant traversed the rejection on pp. 9-12 of the reply filed 6/25/2025. Applicant has simplified the entirety of the obviousness rejection to two paras of Shechter et al, paras. [0095] and [0125], despite examiner citing other paragraphs and three additional references.
Applicant asserts that Shechter et al “provides only generalized guidance regarding which prodrugs would be reversibly linked to the PEG” referring to para [0125]. Applicant asserts that the skilled artisan would not have had a reasonable expectation of success based on “broad” teachings of the cited references. Applicant further states that the instant invention is a class of inventions characterizes being “the unpredictable arts such as chemistry and biology”, citing case law Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001) (reply at p. 11).
Applicant states: the combination of a reversible linker that undergoes hydrolysis that is attached to both a PEG and an oxyntomodulin was not a composition that any one of skill in the art would know to be effective as is newly shown in the examples of the present application. Id.
Applicant asserts that the skilled artisan would not have been able to predict with a reasonable expectation of success that pharmaceutical behavior of a reversibly PEGylated OXM (with low MW) would be similar or greater than a PEGylated OXM (reply at p. 11). Applicant states the “present application newly disclosed and showed that the reversibly-pegylated OXM conjugate now claimed in independent claim 50 is both stable and effective”. Id. Applicant alleges “unexpected” and “surprising” results with respect to AUC (Example 5), and that the claimed conjugates retain co-agonist activity of OXM (dual GLP-1/glucagon receptor agonist) and has an extended half-life (pp. 11-12).
Examiner has considered Applicant’s arguments but is not persuaded.
In this case, the cited references explicitly teach OXM-PEG conjugates. Bossard et explicitly taught OXM-PEG conjugates, as well as an OXM sequence consisting of instant SEQ ID NO:1. Shechter et al. and Shechter 2 taught specific methodologies for reversible/cleavable PEG conjugates that would yield proteins/peptides with improved pharmacokinetic profiles (e.g., AUC), extended the half-life time, bioavailability and efficacy of existing peptide drugs in circulation.
Regarding applicant’s assertion of lack of reasonable likelihood of success in maintaining biological activity in conjugates comprising OXM, MPEP guidelines require a “reasonable” expectation of success, but there is no requirement of a guarantee of success. Conclusive proof of efficacy is not required to show a reasonable expectation of success. Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQe2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367-68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")). See MPEP § 2143.02.
Examiner reminds applicant: Patents and applications are relevant as prior art for ALL they contain. "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989).
It is within the consideration of common knowledge and common sense of the skilled artisan to improve on what is known in the art. Bossard expressly taught OXM-PEG conjugates in which the PEG moiety was attached at the N- or C-termini. Bossard et al. used mPEG-MAL as a reagent in Example 13, as well an OXM peptide consisting of instant SEQ ID NO:1. The references further taught methods of preparing the reversible PEG conjugates comprising Fmoc and FMS, PEG molecular weights of up to 80 kDa, as well as advantages over traditional PEG conjugates (non-reversible). Shechter 2 states that a strategy of reversible pegylation has been applied to several peptide and protein drugs, all of which undergo inactivation by conventional pegylation (p. 2). The Fmoc/FMS technology designed and synthesized two hetero-bifunctional agents of the structures shown in Figure 1. These agents allow the linkage of any peptide or protein containing amino function(s) through a slowly hydrolysable bond. Thus, the prior art specifically teaches that a reversible PEG moiety, comprising the claimed PEG molecular weights, that is advantageous over conventional peg conjugates; e.g. the OXM-peg conjugates taught by Brossard consisting of instant SEQ ID NO:1.
Further regarding Applicant's assertion of unexpected results, even if applicant did properly establish unexpected results, caselaw reiterated the principle from Newell Cos. v. Kenny Mfg. Co., 9 USPQ2d 1417, 1426 (Fed. Cir. 1988) that the mere presence of secondary considerations does not necessarily overcome a strong case of obviousness. See Pfizer Inc. v. Apotex Inc., 82 U.S.P.Q.2d 1321, 1338-39 (Fed. Cir. 2007) (quoting In re Chupp, 816 F.2d 643, 646 (Fed. Cir. 1987)). Secondary considerations are only one factor in determining obviousness.
Shechter et al explicitly taught the following:
[0177] [T]he pegylation technique has been extensively used for modifying molecules, in particular peptide and protein drugs, in an attempt to improve some of its characteristics such as improved stability and solubility, reduced immunogenicity, reduced proteolysis, reduced toxicity, reduced clearance by the kidneys, improved bioavailability, and extended circulating life thus less frequent dosing being required. However, one of the main problems of pegylation is that covalent bonding between the PEG moiety and the drug most often causes loss of biological activity or drastic decrease of pharmacological potency of the drug. For this reason, pegylation is used more for high-molecular weight proteins, that are less likely to be inactivated by the reaction with PEG, but is less frequent for peptides and low-molecular weight proteins.
[0181] [T]he present invention provides a procedure herein designated "reversible pegylation". In this new conceptual approach, that was implemented according to the invention with low molecular-weight polypeptides and proteins, the PEG moiety is not attached directly to the drug, as in the standard pegylation procedure, but rather the PEG moiety is attached directly or through a linker to a moiety … preferably the Fmoc or FMS moiety (i), is highly sensitive to bases and is removable under mild basic conditions. Thus, in this way, a prodrug is obtained that is inactive, but undergoes transformation into the active drug under the physiological conditions of the body. The prodrug has an extended circulation life but the PEG moiety is removed together with the Fmoc or FMS moiety and the drug recovers its full pharmacological potency.
[0182] This novel approach enables the desirable pharmacological features associated with pegylation to be conferred on low molecular-weight peptide and protein drugs that would otherwise have been fully or partially inactivated by this technique. A pharmacologically `silent` conjugate that is `trapped` in the circulatory system releases the covalently-linked parent peptide or protein, with a desirable pharmacokinetic profile. This new approach is expected to extend the life-time, bioavailability and efficacy of existing peptide drugs, and to extend the same in known peptide drugs and peptide drug candidates that may yet be discovered.
[0183] In addition to prolonging life-times in vivo, the inactive but reactivatable PEG-protein conjugate has the profound advantage of maintaining a low circulating level of the active protein drug at any time point after administration.
Shechter et al. at designated paras. Emphasis added.
Thus, Shechter et al. specifically recognized a need to improve on the peptide/protein-PEG conjugates of the prior art through the use of a reversible/cleavable PEG conjugate. Moreover, Shechter et al. specifically taught that such improved peptide/protein-PEG conjugates comprising the cleavable linker would yield proteins/peptides with improved pharmacokinetic profiles (e.g. AUC), and extend the life-time, bioavailability and efficacy of existing peptide drugs in circulation.
Therefore, contrary to Applicant’s assertion of “unexpected results”, the skilled artisan would have, in fact, expected such results as explicitly taught by the cited references.
The rejection is maintained for at least these reasons and those previously made of record.
Examiner further refers Applicant to the cited references at the end of the office action that are provided to rebut Applicant’s arguments relating to “unpredictable arts”.
New Rejection
Claim Rejections - 35 USC § 112
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.
Claim 86 is 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. This is a new rejection necessitated by the amendment filed 6/25/2025.
The metes and bounds of claim 86 are deemed to be indefinite. Claim 86 recites the variable term “n”. This claim limitation is not expressly defined in claim 86, rendering the claim indefinite.
Examiner expressly notes that dependent claims 87 and 88 are not included in this rejection because the claims recite “n is 1 to 3”.
References cited but not relied upon
The following references are provided (again) to rebut Applicant’s assertions that the protein pegylation is an “unpredictable art”. Examiner first notes that the cited reference Shechter et al. (U.S. 2006/0171920) was published in 2006, 5 years before the earliest effective filing date of the instant application, 6/2/2011.
Bailon et al. (Pharmaceutical science and technology today 1: 352-356 (1998) - previously cited)- states that PEG conjugation of biopharmaceuticals is now common practice in efforts to achieve sustained clinical response (abstract). The reference teaches methods for preparing pegylated proteins. The reference further pegylated proteins have reduced immunogenicity, less toxicity compared to the unmodified parent molecule, and allow for slower diffusion back into circulation (e.g., increase stability of the modified protein). This reference is dated from 1998.
Shechter et al. (European Journal of pharmaceutics and biopharmaceutics 70: 19-28 (2008)- previously cited) teach a long-acting insulin based on the following properties: (i) action as a prodrug to preclude supraphysiological concentrations shortly after injection; (ii) maintenance of low-circulating level of biologically active insulin for prolonged period; and (iii) high solubility in aqueous solution. A spontaneously hydrolyzable prodrug was thus designed and prepared by conjugating insulin through its amino side chains to a 40kDa polyethylene glycol containing sulfhydryl moiety (PEG(40)-SH), employing recently developed hetero-bifunctional spacer 9-hydroxymethyl-7(amino-3-maleimidopropionate)-fluorene-N-hydroxysucinimide (MAL-Fmoc-0Su) (abstract).
Fipula et al. (Advanced drug delivery reviews 60: 29-49 (2008)- previously cited) is a review article teaching Releasable PEGylation employs customized linkers that reversibly tether a therapeutic moiety with polyethylene glycol polymers. The choice of releasable PEG linkers may have numerous applications that are insufficiently addressed by stable polymer attachment. Releasable PEGylation provides regeneration of authentic and fully active drug and allows tailored design of critical pharmacological parameters such as the maximal drug concentration and total drug exposure. This provides a prodrug format that combines beneficial attributes of PEGylation with controlled release (abstract).
Veronese et al. (Drug discovery today 10:1451-1458 (2005)- previously cited) teach that PEGylation defines the modification of a protein, peptide or non-peptide molecule by the linking of one or more polyethylene glycol (PEG) chains. This polymer is non-toxic, non- immunogenic, non-antigenic, highly soluble in water and FDA approved. The PEG-drug conjugates have several advantages: a prolonged residence in body, a decreased degradation by metabolic enzymes and a reduction or elimination of protein immunogenicity. Thanks to these favorable properties, PEGylation now plays an important role in drug delivery, enhancing the potentials of peptides and proteins as therapeutic agents.
Veronese (Biomaterials 22:405-417 (2001)- previously cited) is a review article of protein pegylation that was published 10 years before the effective filing date of the instant application. The reference teaches that pegylation is a procedure of growing interest for enhancing the therapeutic and biotechnological potential of peptides and proteins (p. 405). PEG conjugation masks the protein's surface and increases the molecular size of the poly-peptide, thus reducing its renal ultrafiltration, preventing the approach of antibodies or antigen processing cells and reducing the degradation by proteolytic enzymes. Finally, PEG conveys to molecules its physicochemical properties and therefore modifies also biodistribution and solubility of peptide and non-peptide drugs. PEGylation is therefore of interest in applied biotechnology because, upon modification, enzymes may become soluble and active in organic solvent. This property opens new techniques in biocatalysis and in pharmaceutical technology where many insoluble drugs are solubilized by PEG conjugation and thus more easily administered (p. 406). The coming of new PEGylation tools such as dendrimer PEG will further develop the biological and therapeutic applications that, began in the 1970s with the pioneering albumin and catalase PEGylation studies by Davis and Abouchowski, are now expanding to the field of peptide and non-peptide drugs, to immunology, diagnostics and biocatalysis (p. 415).
These references are just a few of the multitude of references available in the prior art relating to protein pegylation. Applicant’s assertion of protein pegylation as allegedly being “an unpredictable art”- is ill-founded. Protein pegylation methodologies and strategies were known in the prior art for many years prior to applicant’s filing of the instant application. Protein pegylation (including reversible pegylation) was well known, predictable, and a firmly established scientific field. Protein pegylation is deemed to be an established art and was not “unpredictable” as applicant asserts.
Conclusion
No claims are allowed.
Claims 49-88 are pending. Claims 49, 58-62 and 64-85 have been withdrawn.
Claims 50-57, 63, and 86-88 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTINA M HELLMAN whose telephone number is (571)272-2836. The examiner can normally be reached M-F 9:00 am-5:30 pm.
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/KRISTINA M HELLMAN/ Examiner, Art Unit 1654