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 .
Status of the application
Receipt of applicant’s remarks and claim amendments filed on 06/12/2026 are acknowledged.
In light of claim amendments, previous 112(b) rejection is withdrawn.
Considering claim amendments, claim 3, in combination with the claimed limitations in claim 1 and exemplified data in the specification (possession), is found free of art.
However, applicants’ arguments for remaining claims are found not persuasive. Accordingly, the previous rejection is maintained and modified to address claim amendments.
Response to Arguments
(i) Applicants argue that as explained in paragraph no. 12 of the Declaration of Daisuke Takahashi, Claim 1 recites cyclizing a linear peptide having at least 8 amino acids in a solvent at a concentration of from 8.6 g/L to 102 g/L, producing a cyclic peptide and a multimeric impurity where the cyclic peptide is dissolved in the solvent.
The peptide in the teachings of Robey is interpreted as ‘a linear peptide has at least 8 amino acids’.
Concentration is a result effective variable. Generally, differences in result-effective variables will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such differences in result-effective variables are critical. "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." In re Aller, 220 F.2d 454, 105 USPQ 233, 235 (CCPA 1955). Accordingly, this type of modification would have been well within the purview of the skilled artisan and no more than an effort to optimize results.
Solubility for any given cyclic peptide for any given solvent differs, and it depends on the structural features of cyclic peptide and properties of solvent. For example, peptide X shows different solubility in solvents ethanol and DMSO or water etc. No peptide shows same solubility in given two or more solvents. So, a skilled person in the art would determine suitable concentrations depends on solvent, based on the structural/chemical properties of cyclic peptides and solvents, through a routine experimentation.
(ii) Applicants argue that as noted in paragraph no. 13 of the Declaration of Daisuke Takahashi, Robey at page 83 defines the term peptomer as a "peptide polymer formed by the crosslinking of a peptide to itself in a specific fashion." A peptomer is one type of non-cyclized peptide impurity. Robey further explains on the same page that "The chances of favoring a peptomer-forming reaction appear to be best at high concentrations (~10 mg/mL) of the bromoacetylated, cysteine-containing peptide dissolved or suspended in an aqueous buffer at pH 6-8".
As explained above, concentrations are result effective variables and it depends on peptide structure and solvents. Since claims are very generic, and cited art reads broadly claimed subject matter.
(iii) Applicants argue that as explained in paragraph no. 15 of the Declaration of Daisuke Takahashi, of the other cited references, Takahashi and Kim et al. are each directed to purification of cyclic peptides but do not discuss cyclizing a linear peptide. Veber et al. describes cyclizing linear hexapeptides, rather than linear peptides having at least 8 amino acids. Isidro-Llobet et al. is directed to amino acid protecting groups and provides no teaching of cyclizing a linear peptide.
Purpose of these secondary art is to show the established solvents in the purification of cyclic peptides. Purpose of Isidro-Llobet is to show the art established protecting groups. Applicants fail to explain why the teachings of these art not applicable to the claimed generic subject matter.
(iv) Applicants argue that as explained in paragraph no. 17 of the Declaration of Daisuke Takahashi, the above remarks [pointed to previous (v) of examiner’s response] appear to be a misunderstanding of the Applicants' arguments in the response filed on January 16, 2026, at page 18, lines 9 to 12. Applicants' reference to "step (3)" was to show that protecting groups may or may not be present in the cyclic peptide during step (2), meaning that the present method for producing a cyclic peptide is shown to be effective regardless of the presence or absence of hydrophobic protecting groups. Claim 1 already describes that the protecting groups and pseudo solid phase protecting groups are optional. As the presence (or absence) of protecting groups affects the physical properties of the whole molecule, the method is shown to be highly versatile. This is evident from the below table summarizing the conditions of the inventive examples of the specification, where linear peptides at starting concentrations of from 8.6 g/L to 102 g/L were cyclized and had purity improvements of at least 9%.
Even if protecting groups are optional, still cited art reads applicants claimed subject matter, since the breadth of claims are very broad. Please note that the cited art teaches with protecting groups, and so, still cited art reads claimed subject matter.
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 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 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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 4-5, 7-17, 22 and 24-30 are rejected under 35 U.S.C. 103 as being unpatentable over Robey (Methods in Molecular Biology, vol.35: Peptide Synthesis Protocols, edited by M.W.Pennington and B.M.Dunn, 1994, Chapter 6, pages 73-90) in view of Takahashi (US 2012/0059149 A1, which is equivalent to WO 2012/029794), Kim (US 2014/0142031 A1), Veber (US 4,108,987) and Isidro-Llobet et al (Chem.Rev., 2009, 109, 2455-2504).
In view of elected species and in combination with elected Example 1, the claims may be summarized as follows:
A method for producing a cyclic peptide comprising:
-preparing a linear peptide optionally having a protecting group and/or a pseudo solid phase protecting group in the N-, C-terminal and/or side chains of amino acids;
-deprotecting a site to be cyclized in the linear peptide;
-providing unprotected linear peptide, wherein peptide comprising Cys and wherein N-terminus of peptide is coupled with chlorobutyryl group;
-cyclizing a linear peptide through the N-terminal chlorobutyryl group and thiol group of Cys, which results in the mixture of the cyclic peptide having multimeric impurity;
-purifying the cyclic peptide by adding a poor solvent and good solvent to a mixture of the cyclic peptide and multimeric impurity, and filtering off the multimeric impurity as an insoluble material;
-removing all protecting groups;
wherein the resulted cyclic peptide has a C-S type bonding.
For claim 1:
Robey teach cyclization of linear peptide through the N-terminal chlorobutyryl group and thiol group of Cys in the peptide, wherein the resulted cyclic peptide comprises C-S type bond. [see section “3.5. Synthesis of Cyclic Peptides from Bromoacetylated Peptides” in pages 81-83]. Robey further suggest that “it may be necessary to use chloroacetyl moiety instead of bromoacetyl moieties if the bromoacetyl appears to be unacceptably reactive” [see second paragraph in page 81]. In Fig.2, Robey suggests <1 mg/ml of protein concentration before it gets cyclized. Robey further teach purification of the cyclized peptide by reverse-phase HPLC using acetonitrile, wherein cyclic peptide can be identified from the elution profile, wherein cyclized peptide will appear in the eluant earlier than the noncyclized peptide [see pages 81-83]. The noncyclized peptide is interpreted as applicants’ multimeric impurity.
The peptide in the teachings of Robey is interpreted as ‘a linear peptide has at least 8 amino acids’.
Robey further teaches linear peptide having protecting groups both manual and automated approaches [see sections 3.1 to 3.4 under].
With regard to new limitation on purity determination, through it is a trivial, however, it is an abstract idea, and so, it does not have any weight. It can also be interpreted as ‘product by process’ claim format, and so the process steps do not have any weight.
The differences between Robey and instant claim(s) as follows:
(i) Robey is silent applicants elected peptide;
(ii) Robey is silent applicants elected chlorobutyryl group at N-terminus;
(iii) Robey is silent on applicants recited concentrations and purity of cyclic peptide.
With regard to (i) of above, the teachings of Robey is a protocol to make a cyclic peptides from their corresponding linear peptides and therefore, the disclosed protocol with step by step directions are expected to work for cyclization of applicants elected linear peptide, absent evidence to the contrary.
With regard to (ii) of above, Robey suggests both chloroacetyl moiety and bromoacetyl moieties and both works depends on conditions [see second paragraph in page 81]. So, the real difference is chloroacetyl vs chlorobutyryl. So, the difference between the claimed compound and the cited compound is the chain length, C2 vs C4. Since C2 is considered as a homolog of C4 length, these compounds are considered equivalent. The MPEP 2144.09 states “Compound which are….homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F. 2d 457, 195 USPQ 426 (CCPA 1977).
With regard to (iii) of above, concentration is a result effective variable. Generally, differences in result-effective variables will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such differences in result-effective variables are critical. "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." In re Aller, 220 F.2d 454, 105 USPQ 233, 235 (CCPA 1955). Accordingly, this type of modification would have been well within the purview of the skilled artisan and no more than an effort to optimize results.
Solubility for any given cyclic peptide for any given solvent differs, and it depends on the structural features of cyclic peptide and properties of solvent. For example, peptide X shows different solubility in solvents ethanol and DMSO or water etc. No peptide shows same solubility in given two or more solvents. Claim language is nothing but a quiz language and are very generic and so, all possible solvents will not show recited solubility property, but may be few solvents close to the claimed concentrations, depends on their structural properties. So, a skilled person in the art would determine suitable solvent, based on the structural/chemical properties of cyclic peptides and solvents, through a routine experimentation.
With regard to purity, again it depends on choice of solvents and solubility of peptides. As explained above, a skilled person in the art always choose suitable solvents based on the structural features of peptides and solvents, through routine experimentation and arrive at applicants claimed range with a reasonable expectation of success.
For claim 2:
Specification define good solvent as a solvent capable of dissolving the cyclic peptide of interest, such as chloroform, dichloromethane, dimethylformamide, THF etc.
Separation of peptides based on solvent separation, in which peptide dissolve in specific solvents and impurities get dissolved in different solvent or layer, and this technique is well known in the art. So, a skilled person in the art can determine suitable solvents to purify peptide based on the properties of expected impurities, through a routine experimentation.
For example, Takahashi teaches purification or separation peptides from impurities by addition hydrophilic solvent, wherein peptide gets dissolved into hydrophilic solvent layer, wherein hydrophilic solvents are selected form acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide etc, and N,N-dimethylformamide is more preferable [see 0143-0145; claims 22-23].
Since claims require both poor solvent and good solvent in combination or adding separately, but their function is to dissolve peptide, which is organic layer. In addition, Takahashi teach both acetonitrile and dimethylformamide for extracting peptides based on the solubility properties of peptides.
In addition, applicants defined other solvent, viz., methanol and chloroform etc., is also well known in the purification of cyclic peptides. For example, Kim teaches chloroform or methanol or combination applied in the purification cyclic peptide [see claim 8-10]. In another example, Veber teaches chloroform in the purification of cyclic peptides [see example 2].
Teachings of above art is equally applicable to other peptides or cyclic peptides, absent evidence to the contrary. Generally, selection of solvent(s) is based on the properties of peptides, impurities and can also be based on economical or environmental reasons. If applicants think a specific solvent is critical, then applicants are invited to show the comparative data with various solvents and recite the specific solvent(s) in the independent claim. In its absence, this limitation is obvious over the prior art.
For claim 4:
Robey teaches that if a cysteine is present in a bromoacetyl-containing peptide, it is very likely that the SH will attack the bromoacetyl to form inter- and/or intramolecular thioether bridges [see first paragraph in section 3.5 in page 81]. Therefore, the protected C-terminal or unprotected C-terminal does not affect the cyclization reaction. Robey further teaches that the cyclization occurs between N-terminal and side chain amino acids, i.e, cyclic peptide comprises a C-S type bonding [see Fig.2 in page 82].
For claim 5:
Applicants’ specification define the pseudo-solid-phase protecting groups and acknowledged that these were known in the art and also cited relevant art.
For example, Takahashi [US 2012/0059149 A1, which is equivalent to specification cited WO 2012/029794] teaches various pseudo-solid-phase protecting groups and their advantages in extracting peptides based on layer-separating extraction [see Table 1 and 2]. So, incorporating pseudo-solid-phase protecting groups increases solubility of peptides in hydrophilic solvents, such as acetonitrile and DMF etc., which makes the purification more efficient. Therefore, a skilled person in the art would be motivated to incorporate pseudo-solid-phase protecting groups in the peptide of interest.
For claims 7-8:
Takahashi teach use of acetonitrile and DMF as hydrophilic solvents, which dissolves peptides, specifically depends on the property of peptides. Similarly, acetonitrile and DMF may differ in their properties for dissolving divergent peptides, because their polarities are different. In others words, for a given peptide, the solubilities are going to be different with respect to different solvents, such as acetonitrile and DMF etc..
The multimeric impurities are more hydrophobic and may not get dissolved in hydrophilic solvents or water etc, and this expected. Moreover, a skilled person in the art determine suitable solvents for peptides based on the properties of amino acids in the peptide, which is a common and routine practice in the art.
For claim 9:
Robey teaches that if a cysteine is present in a bromoacetyl-containing peptide, it is very likely that the SH will attack the bromoacetyl to form inter- and/or intramolecular thioether bridges [see first paragraph in section 3.5 in page 81]. Therefore, the protected C-terminal or unprotected C-terminal does not affect the cyclization reaction. Robey further teaches that the cyclization occurs between N-terminal and side chain amino acids, i.e, cyclic peptide comprises a C-S type bonding [see Fig.2 in page 82].
For claim 10:
Applicants’ specification define the pseudo-solid-phase protecting groups and acknowledged that these were known in the art and also cited relevant art.
For example, Takahashi [US 2012/0059149 A1, which is equivalent to specification cited WO 2012/029794, cited in the specification] teaches various pseudo-solid-phase protecting groups and their advantages in extracting peptides based on layer-separating extraction [see Table 1 and 2]. So, incorporating pseudo-solid-phase protecting groups increases solubility of peptides in hydrophilic solvents, such as acetonitrile and DMF etc., which makes the purification more efficient. Therefore, a skilled person in the art would be motivated to incorporate pseudo-solid-phase protecting groups in the peptide of interest.
For claims 11-12:
Takahashi teach use of acetonitrile and DMF as hydrophilic solvents, which dissolves peptides, specifically depends on the property of peptides. Similarly, acetonitrile and DMF may differ in their properties for dissolving divergent peptides, because their polarities are different. In others words, for a given peptide, the solubilities are going to be different with respect to different solvents, such as acetonitrile and DMF etc..
The multimeric impurities are more hydrophobic and may not get dissolved in hydrophilic solvents or water etc, and this expected. Moreover, a skilled person in the art determine suitable solvents for peptides based on the properties of amino acids in the peptide, which is a common and routine practice in the art.
For claim 13:
Robey teaches that if a cysteine is present in a bromoacetyl-containing peptide, it is very likely that the SH will attack the bromoacetyl to form inter- and/or intramolecular thioether bridges [see first paragraph in section 3.5 in page 81]. Therefore, the protected C-terminal or unprotected C-terminal does not affect the cyclization reaction. Robey further teaches that the cyclization occurs between N-terminal and side chain amino acids, i.e, cyclic peptide comprises a C-S type bonding [see Fig.2 in page 82].
For claim 14:
Robey further teach purification of the cyclized peptide by reverse-phase HPLC using acetonitrile, wherein cyclic peptide can be identified from the elution profile, wherein cyclized peptide will appear in the eluant earlier than the noncyclized peptide [see pages 81-83]. There is no addition of poor solvent etc. and, so, it meets claim limitation.
For claims 15-16:
Takahashi teach use of acetonitrile and DMF as hydrophilic solvents, which dissolves peptides, specifically depends on the property of peptides. Similarly, acetonitrile and DMF may differ in their properties for dissolving divergent peptides, because their polarities are different. In others words, for a given peptide, the solubilities are going to be different with respect to different solvents, such as acetonitrile and DMF etc..
The multimeric impurities are more hydrophobic and may not get dissolved in hydrophilic solvents or water etc, and this expected. Moreover, a skilled person in the art determine suitable solvents for peptides based on the properties of amino acids in the peptide, which is a common and routine practice in the art.
For claim 17:
Removing various protecting groups are well documents in the art. For example, Takahashi teach removing various protecting groups [see examples]. Isidro-Llobet et al teach various protecting groups for amino acids and their removal methodologies [see whole review article].
For claim 22:
Robey teaches a cyclization of linear peptide, and so, it is interpreted as a peptide having unprotected N-, C-terminal and/or desirable side chains of constituent amino acids, which is suitable for cyclization reaction.
For claim 24:
Robey teaches that the resulted cyclic peptide comprises a C-S type bonding [see Fig.2 in page 82].
For claim 25-27:
Robey further teach purification of the cyclized peptide by reverse-phase HPLC using acetonitrile, wherein cyclic peptide can be identified from the elution profile, wherein cyclized peptide will appear in the eluant earlier than the noncyclized peptide [see pages 81-83]. Kim and Veber teaches applicants good solvents, which are methanol, chloroform etc.
It appears that some solvents are common in both poor and good solvents in the claims. Regardless, selecting suitable solvents depends on the properties of cyclic peptide and solvents, and so, accordingly, a skilled person in the art would always choose desirable solvents based on the properties of components through a routine experimentation.
For claims 28-29:
See above For claim 1, 4-5, 7-9 and 25-27.
For Claim 29:
See For claims 25-27 above.
Based on the above established facts from the cited prior art, it appears that all the claimed elements, i.e, haloacetyled amino acids and their utilities in cyclization with SH groups of Cys moieties in peptides, solvent systems in purification of peptides etc., were known in the prior art, and one skilled person in the art could have combined the elements as claimed by known relationships, with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art.
The motivation to combine the art can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. See MPEP 2144.07. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention by taking the advantage of the teaching of the above cited reference and to make the instantly claimed method with a reasonable expectation of success.
Allowable Subject Matter
Claim 3 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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 SUDHAKAR KATAKAM whose telephone number is (571)272-9929. The examiner can normally be reached 8:30 am to 5 pm.
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SUDHAKAR KATAKAM
Primary Examiner
Art Unit 1658
/SUDHAKAR KATAKAM/Primary Examiner, Art Unit 1658
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