DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. The Amendments filed on May 6, 2026, has been received and entered.
Claim Disposition
3. Claims 6 and 8-11 have been cancelled. Claims 1-5, 7 and 12-14 are pending. Claims 1-5 and 7 are under examination. Claims 12-14 are withdrawn from consideration as directed to a non-elected invention.
Claim Objection
4. Claims 1-5 and 7 are objected to because of the following informalities:
For clarity and consistency, it is suggested that claim 1 is amended to recite “SEQ ID NOs:” instead of “SEQ ID NOS:” (see claim 5 also with similar issues). For clarity the percentage of sequence identity should be followed by the specific sequence notation, for example, “at least 80% sequence identity to SEQ ID NO:1”. For clarity and precision of claim language it is suggested that claim 1 is amended to read, “….having the [[a modification meeting the conditions]] set forth in (i) to (iv) introduced into….”. The dependent claims hereto are also included.
For clarity it is suggested that claim 2 is amended to read, “….[[which is]] wherein the polypeptide is a single domain peptide comprising……”. See also claim 3 with similar language.
Appropriate correction is required.
Claim Rejections - 35 U.S.C. § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
5. Claims 1-5 and 7 are rejected under 35 U.S.C. 112, first paragraph, as containing subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and or use the invention.
The claimed invention is directed to a polypeptide comprising at least one immunoglobulin-binding domain as set forth in claim 1 (see claim 1 in its entirety).
The polypeptide comprises substitutions on certain positions and has been amended to recite that the positions can be found in SEQ ID NOs: 1-15. The claimed invention also encompasses a large variable genus with the recitation of “wherein one or more amino acid sites without the modification are substituted, added, inserted and/or deleted and wherein the immunoglobulin binding domain has equivalent or higher alkaline stability….. and the recitation of at least 80% or more sequence identity with no corresponding alignment to a specific structure. The recitation of equivalent or higher could simply be one more; and several modifications are listed in claim 1 as ‘unsubstituted’ and position 41 is the only position that is definitely substituted and there is no nexus with ‘at least 80% sequence identity’ and a single mutation in the structures.
The claimed invention broadly comprises modifications in the structures set forth in the claim that may not garner activity or safe guard any active sites. The invention is not adequately described because it encompasses a large variable genus of structures that have not been correlated with function or retention of the native function. The art generally discloses that a single amino acid change can be detrimental to structure-function relationship, and the claimed invention encompasses an enormous amount of changes. The claimed invention as set forth in claim 1 encompasses fragments which means amino acid residues can be added, substituted, deleted etc.
The claimed invention is not commensurate in scope with the disclosure in the specification and applicant has not demonstrated possession of the entire genus encompassed in the claims. The specification fails to provide any additional representative species of the claimed genus to show that applicant was in possession of the claimed genus. A representative number of species means that the species which are adequately described are representative of the entire genus. The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. The claimed invention is also directed to a therapeutic composition with the ADI and a pharmaceutically acceptable carrier, however, there are no indicia in the claims as to what is being treated and who the subject is (for example, cancer patient).
Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus. The claimed genus of polypeptides could include non-functional proteins or proteins with a different function than the one described. Therefore, the genus of claimed polypeptides encompasses widely variant species. Based on the unlimited variations contemplated one skilled in the art would at best expect a protein that is different or at worst a protein that is not functional. Moreover, Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir.1991), states that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed" (See page 1117). The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed" (See Vas-Cath at page 1116). The skilled artisan cannot envision the detailed chemical structure of the encompassed genus of polypeptides, and therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993).
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that the applicant had possession of the claimed invention at the time the instant application was filed.
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.
6. 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.
7. Claim(s) 1-5 and 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Pastor et al. (2007, of record in the application) in view of JP2016-523959 (record in the application), JP2013-256479 (of record in the application), WO2012/165544 (of record in the application) and JP2010-156687(of record in the application).
Pastor et al. discloses that the hydrophobic core of the B domain of Protein A was redesigned and mutants with high thermal stability were obtained by screening based on binding affinity with IgG; and that mutants were obtained by replacing the amino acid at position 44 (corresponding to position 41 in SEQ ID NOs:1 to 15 of the present application) with phenylalanine or threonine (see in particular abstract; page 14924, left column, paragraph 2 to page 14930, right column; paragraph 2; Tables 1 and 2; figure 10). Moreover, the reference describes the amino acid sequence of a peptide named H1-H2-H3p2 as one of the above mentioned mutants (Table 2). Therefore, the amino acid sequence becomes a sequence wherein, the amino acid sequence represented by SEQ ID NO:7 of the present application, three amino acid residues are added at the N-terminal side, the amino acid residue at position 41 is replaced by Phe, and the amino acid residue at position 44 is replaced by Val. In this case, as also described in reference (see in particular, page 14929, right column, paragraph 2), because the replacement of the amino acid residue at position 47 (corresponding to position 44 in SEQ ID NOs: 1 to 15 of the present application) in the mutant of the present reference is conserved, it is extremely likely that the substitution and addition of the amino acids to the terminus did not cause a decrease in stability or a decrease in IgG elution capability. Moreover, as set forth in the description of the present application (paragraph [0106]), the replacement of the serine residue at position 44 in the mutant of the present reference (corresponding to position 41 in SEQ ID NOs: 41 in SEQ ID NOs:1 to 15 of the present application) with a hydrophobic residue leads to an increase in residual activity following an alkaline treatment and an increase in the elution rate under weakly acidic conditions.
The primary reference does not per se teach a replacement of glutamine residue, however, the secondary reference teaches replacing the glutamine residue at position 9 of the B or C domain of Protein A with an amino acid residue such as alanine; and that the invention provides both a polypeptide multimer and a separation matrix (see in particular abstract; and claims). Further the tertiary reference teaches that the elution properties are excellent under weakly acidic conditions in mutants wherein the glutamic acid residue at position 15 of Protein A was replaced by a histidine residue; and that one to three units of the sequence of the Protein A mutant were joined together (see in particular, abstract, claims and paragraph [0107]). Moreover, the fourth reference discloses mutants of Protein A with decreased affinity in the acidic region and an antibody capture agent. The fourth reference also states that substitutions of the amino acid residues at positions 9, 15, 24, etc., were performed; that a preferred targeted position for mutation can be selected not only in the B domain but also in the D, A, C and Z domains; and that a tandem-type amino acid sequence increases the effectiveness of antibody binding affinity (see in particular abstract, paragraphs [0031-0032], [0042-0043]; examples). Additionally, the fifth reference describes mutants wherein substitutions were performed at position 24 of the E, D, A, B, C and Z domains of Protein A, and an alkaline stable ligand comprising two or more domains (see in particular, claims and Table 1).
The primary reference does not describe a mutant in a domain other than the B domain of Protein A, but as described in the secondary and fourth/fifth references, for example, it was common technical knowledge before the effective date of the present application that a mutation site in a certain domain of Protein A can be selected as a mutation site in an different domain, and therefore a person skilled in the art could have easily prepared the same kind of mutant in a domain other than the B domain based on common technical knowledge available before the effective date of the present application, claim 1 is deemed obvious. Regarding claim 2 it does not create any new difference and claim 3 increases binding affinity (as also seen in the second to fifth references) to an antibody by joining multiple domains of Protein A together was widely known before the effective date of the present application, a person skilled in the art could have easily obtain a multiple-domain peptide in the invention described in primary reference based on the technique that was widely known before the priority date of the present application. Further claim 4, 5 and 7 are obvious although the primary reference does not describe performing the amino acid substitutions stipulated in these claims. It is clear, however, that applying the Protein A mutants described in the primary reference, which were obtained as mutants with excellent thermal stability, to antibody purification, which is a widespread use of Protein A, and then inserting additional mutations to suit the desired properties during antibody purification is an obvious problems for persons skilled in the art. Furthermore, as properties and the mutation sites that impart said properties, it would not have been particularly difficult for a person skilled in the art to choose properties such as the alkaline stability and the dissolution properties under acidic conditions described in the second to fifth references as well as the mutation sites that impart these properties. Regarding claim 6 it does not create any new difference. In addition, although the primary reference teaches Phe, there is a limited set of hydrophobic amino acids and one of ordinary skill in the art in the field would know to try all of the nine standard ones (aliphatic: alanine, valine, leucin, isoleucine, methionine and proline; and aromatic: phenylalanine, tryptophan and tyrosine) based on routine optimization and with a high expectation of success.
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to arrive at the claimed invention as a whole because the combined teaching of the references renders the claims as obvious. The references are considered to be analogous art, thus motivation to combine exists.
Moreover, the Supreme Court pointed out in KSR, “a patent composed of several elements is not proved obvious merely by demonstrating that each of its elements was, independently, known in the prior art.” KSR, 127 S. Ct. at 1741. The Court thus reasoned that the analysis under 35 U.S.C. 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the “inferences and creative steps that a person of ordinary skill in the art would employ.” Id. at 1741. The Court further advised that “[a] person of ordinary skill is…a person of ordinary creativity, not an automation.” Id. at 1742. Therefore, the claimed invention was obvious to make and use at the time the invention was made and was prima facie obvious.
Response to Arguments
8. Applicant’s comments have been considered in full. Withdrawn objections/rejections will not be discussed herein as applicant’s comments are moot. Note that new objections and a rejection under 112, first paragraph has been instituted for the reasons set forth above based on amendments made to the claims. Note also that the rejection under 103 remains for the reasons stated above and herein. Applicant traverses the rejection stating that Phe has been removed from the claim language. However, as stated above, there are limited set of hydrophobic amino acids and the ordinary skill worker would for routine optimization try others. The claimed invention is focused on substitutions producing equivalent or higher alkaline stability with the hydrophobic amino acids or hydrophobic aliphatic side chain (all of these are well established in the art) and there is no results that have been claimed wherein the improvement is vast, such as a 2 fold or 5 fold increase. Applicant is claiming equivalent or higher and ‘higher’ is not defined, thus reasonable to conclude that it could be obtained absence evidence to the contrary with any of the 9 hydrophobic amino acids. Thus, the claimed invention remains obvious.
Conclusion
9. No claims are presently allowable.
10. Applicant’s amendment necessitated the new/modified ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HOPE A ROBINSON whose telephone number is (571) 272-0957. The examiner can normally be reached 9-5pm on Monday to Friday.
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/HOPE A ROBINSON/Primary Examiner, Art Unit 1652
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