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 .
Summary
Claims 1-12 and 16-25 are pending in this office action. Claims 13-15 are cancelled. All pending claims are under examination in this application.
Priority
The current application filed on February 22, 2023 is a 371 of PCT/EP2021/072364 filed August 11, 2021. The current application claims foreign priority to EP20192331.5 filed August 24, 2020.
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 non-obviousness.
Claims 1-12 and 16-25 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (Dissertation, published April 2020) in view of Mohtar et al. (Molecular & Cellular Proteomics, 2018), Ruiz-Opazo et al. (US2019/0083595A1), Kentsis et al. (US2019/0276509A1) and Kondo et al. (WO2019/212031A1).
[The Examiner is going to introduce each reference and then combine them where appropriate to reject the instant claims. The Examiner is going to rely on the English translation of Kondo et al. within US2021/0163537A1 instead of the WO2019/212031A1 publication. All citations for Kondo et al. refer to the US publication which is the same patent family.]
1. Zhang
Zhang teach anterior gradient 2 which promotes PDAC progression by directing RNA polymerase II nuclear import (see title). Additionally, Zhang disclose Agr2 (anterior gradient 2) encodes an oncogenic endoplasmic reticulum (ER)-resident protein disulfide isomerase that is universally expressed by human adenocarcinomas. Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. So far, the function of Agr2 in PDAC is not fully uncovered. We used a well-established mouse model of caerulein-induced pancreatitis and inflammation-accelerated KrasG12D-driven PDAC. The dynamic formation of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) was quantified using immunohistochemistry. To study the function of Agr2 in carcinogenesis, a mouse model with either conditionally ablated or over-expressed Agr2 in pancreatic epithelial cells was used. A set of in vitro biochemical assays was carried out to investigate the potential molecular mechanisms. Hereby, we observed that p53 is transiently suppressed during the phenotypic progression from ADM to PanIN lesions. Agr2, a putative p53 inhibitor, is found to be responsible for p53 suppression, as the pancreas-specific Agr2 ablation inhibits this phenotypic progression with concomitant p53 activation while the pancreas-specific Agr2 overexpression impairs p53 activation. Mechanistically, Agr2 binds to Polr2a (RNA polymerase II subunit a), which is the catalytic subunit of the RNA polymerase II (Pol II). As such, Agr2 directs Pol II nuclear import via its C-terminal nuclear localization signal. Loss of Agr2 function causes inadequate Pol II activation, and the resulting transcriptional stress activates p53 in an ATR-dependent manner. Compellingly, it dramatically sensitizes PDAC cell lines with wild-type TP53 to a specific Pol II inhibitor: a-amanitin. In summary, the Agr2/Pol II axis constitutes a reasonable target for PDAC containing wild-type p53 (see abstract).
2. Mohtar et al.
Mohtar et al. teach the sequence-specific peptide-binding activity
of the protein sulfide isomerase AGR2 directs its stable binding to the oncogenic receptor EpCAM (see title). In addition, Mohtar et al. disclose AGR2 is an oncogenic endoplasmic reticulum (ER)-resident protein disulfide isomerase. AGR2 protein has a relatively unique property for a chaperone in that it can bind sequence-specifically to a specific peptide motif (TTIYY). A synthetic TTIYY-containing peptide column was used to affinity-purify AGR2 from crude lysates highlighting peptide selectivity in complex mixtures. Hydrogen-deuterium exchange mass spectrometry localized the dominant
region in AGR2 that interacts with the TTIYY peptide to within a structural loop from amino acids 131–135 (VDPSL). A peptide binding site consensus of Tx[IL][YF]
[YF] was developed for AGR2 by measuring its activity against a mutant peptide library. Screening the human proteome for proteins harboring this motif revealed an
enrichment in transmembrane proteins and we focused on validating EpCAM as a potential AGR2-interacting protein. AGR2 and EpCAM proteins formed a dose-dependent protein-protein interaction in vitro. Proximity ligation assays demonstrated that endogenous AGR2 and EpCAM protein associate in cells. Introducing a single alanine mutation in EpCAM at Tyr251 attenuated its binding to AGR2 in vitro and in cells. Hydrogen-deuterium exchange mass spectrometry was used to identify a stable binding site for AGR2 on EpCAM, adjacent to the TLIYY motif and surrounding EpCAM’s detergent binding site. These data define a dominant site on AGR2 that mediates its specific peptide-binding function. EpCAM forms a model client protein for AGR2 to study how an ER-resident chaperone can dock specifically to a peptide motif and regulate the trafficking a protein destined for the secretory pathway (see abstract).
3. Ruiz-Opazo et al.
Ruiz-Opazo et al. teach methods for treating netosis and neutrophil activation (see title). Also, Ruiz-Opazo et al. disclose that described herein are methods and compositions relating to methods of inhibiting neutrophils, e.g., inhibiting NET
release or NETosis, by means of a DEspR inhibitor, e.g., an anti-DEspR antibody reagent. In some embodiments, the methods can relate to the treatment of a disease, e.g., cancer or a disease wherein neutrophils; NETs; or NETosing or NETting neutrophils contribute to pathogenesis, chronicity, or worsening of disease. In some embodiments, the DEspR inhibitor can be a bi-specific reagent or an antibody-drug
conjugate (see abstract).
4. Kentsis et al.
Kentsis et al. teach agents and methods for treating CBP-dependent cancers (see title). Furthermore, Kentsis et al. disclose single chain peptides comprising either a cell penetrating HIV-TAT peptide sequence and a MYB:CBP complex interfering peptide sequence from MYB, or comprising a cell penetrating HIV-TAT peptide sequence, a CBP binding peptide sequence from CREB and a MYB:CBP complex interfering peptide sequence from MYB, are provided for use in preventing MYB:CBP complex formation and downstream events leading to cancer, in particular a leukemia. Both L-amino acid single chain peptides and retro-inverso single chain peptides are provided (see abstract).
5. Kondo et al.
Kondo et al. teach peptides and use therefor (see title). Additionally, Kondo et al. disclose that this peptide is composed of an amino acid sequence represented
by general formula (I), and has a high degree of accumulation in cancer cells or cancer tissue in a digestive system. [In general formula (I), X11 is a peptide residue
composed of an amino acid sequence of (a) or (b) below: (a) an amino acid sequence represented by any of SEQ ID NOs 1 to 3, (b) an amino acid sequence including a sequence in which one or two amino acids have been deleted, substituted or added in an amino acid sequence represented by any of SEQ m NOs: 1 to 3; Y11 is a peptide linker composed of an amino acid residue of at least 1 but not more than 10 amino
acids, wherein each amino acid residue is independently a glycine residue, a praline residue, a serine residue a cysteine residue or a lysine residue; X12 is either a peptide residue composed of an amino acid sequence of (a) or (b) above, or a retro-inverso peptide residue thereof; and n11 represents an integer of at least 1 but not more than 9] (see abstract).
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Combination of Zhang and Mohtar et al.
Regarding instant claims 1-4, Zhang and Mohtar et al. teach a peptide comprising the sequence of NTAIYY. The citations of Zhang and Mohtar et al. which correspond with the instant claim limitations are presented within Table I.
Table I
Instant Claim 1
Zhang and Mohtar et al. Citations
A peptide comprising an amino acid sequence NTXIYY (SEQ ID NO:1), wherein X=A (SEQ ID NO:2) or T (SEQ ID NO:3),
Zhang discloses the following amino acid sequence:
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which identifies NTAIYY (see page 60 within Zhang).
wherein the peptide does not have a length greater than 30 amino acid residues in total.
Zhang discloses wherein said peptide is a hexapeptide. Zhang discloses the Polr2a protein sequence that binds to Agr2 (aa 1173-1177), TAIYY (see page 60 within Zhang). Moreover, the residue at position 1172 is N.
Additionally, Mohtar et al. disclose that peptide A4 with the sequence HLPTTIYYGPPG (containing the key functional pentapeptide
sequence italicized) was previously shown to bind Agr2 (see page 742, 1st paragraph; and abstract; both within Mohtar et al.).
Therefore, a skilled artisan (POSITA; person of ordinary skill in the art) would be able to identify either hexapeptide NTAIYY or NTTIYY, which would be synthesized under routine experimental conditions and then biologically evaluated using the combined teachings of both Zhang and Mohtar et al.
The remainder of the instant claims are directly or indirectly taught by the combination of Zhang and Mohtar et al.
Regarding instant claim 5, Zhang and Mohtar et al. teach further comprising an N-terminal protecting group (PG) and/or a C-terminal protecting group. Polypeptide solid-phase synthesis (SPPS), which can be used to afford the desired peptide would generate either the N-terminus or C-terminus (or both) protected variant(s). One of the most common orthogonal protecting groups used in SPPS are the 9-fluorenylmethyloxycarbonyl (Fmoc; N-terminal PG) and the tert-butyl ester (t-Bu; C-terminal PG).
Regarding instant claims 17-20, Zhang and Mohtar et al. teach a method for treating a cancer tumour in a patient, said cancer tumour being characterised by having a wildtype-version of the TP53 gene, and not having a mutated version of the TP53 gene, wherein, in said method, a peptide according to claim 1 is administered to a patient having or suspected of having or developing a cancer tumour.
Both the Zhang and Mohtar et al. disclosures in combination support the development of a method of administration from their biological data (see title and abstracts within Zhang and Mohtar et al.). Zhang discloses the Agr2 promotes early pancreatic progression, which renders obvious the use of Agr2 activity inhibitors for the treatment of at this disease (see title and abstract within Zhang). In addition, Zhang discloses PDAC (pancreatic cancer) cell lines with wild-type TP53 to a specific Pol II inhibitor (see abstract within Zhang; also see pages 5-9 within Zhang).
Regarding instant claim 16, Zhang and Mohtar et al. teach a method of sensitizing a cancer tumour to the action of an anti-cancer agent in a patient, wherein, in said method, a peptide according to claim 1 is administered to a patient having or suspected of having or developing a cancer tumour, and wherein said anti-cancer agent is administered to said patient concomitantly with said administration of said peptide.
Zhang discloses that mechanistically, Agr2 binds to Polr2a (RNA polymerase II subunit a), which is the catalytic subunit of the RNA polymerase II (Pol II). As such, Agr2 directs Pol II nuclear import via its C-terminal nuclear localization signal. Loss of Agr2 function causes inadequate Pol II activation, and the resulting transcriptional stress activates p53 in an ATR-dependent manner. Compellingly, it dramatically sensitizes PDAC cell lines with wild-type TP53 to a specific Pol II inhibitor: a-amanitin. In summary, the Agr2/Pol II axis constitutes a reasonable target for PDAC containing wild-type p53 (see abstract within Zhang).
Therefore, a skilled artisan (POSITA) would develop a method to be able to use this data and conclusion from Zhang and sensitize a cancer tumour to the action of an anti-cancer agent in a patient.
Combination of Zhang, Mohtar et al., and Kentsis et al.
Regarding instant claim 6, Zhang, Mohtar et al., and Kentsis et al. teach wherein the N-terminal protecting group has the general formula -C(O)-R, wherein R is selected from the group consisting of H, unsubstituted or substituted alkyls, and unsubstituted or substituted aryls; and wherein the C-terminal protecting group is-NR1R2, R1 and R2 being independently selected from H and C1-C10 alkyl, said -NR1R2 thus forming an amide bond at the C-terminus of said peptide. Kentsis et al. is in the field of cancer research (see title and abstract within Kentsis et al.). Kentsis et al. disclose in one embodiment, the single chain peptide has the D-amino acid sequence [Ac]-KLENETSMLLLELEKIRKGGRRRQRRKKRGY-[NH2] (SEQ ID NO: 1). [Ac] represents an acetyl group at the N terminus, and [NH2] represents an amide at the C terminus (see paragraph [0011] within Kentsis et al.). The acetyl group is defined by -C(O)-methyl (unsubstituted alkyl). Therefore, a skilled artisan (POSITA) would be motivated to cap the N terminus of the polypeptide with an acetyl group, and the C terminus with a [NH2] group.
Combination of Zhang, Mohtar et al., and Ruiz-Opazo et al.
Regarding instant claims 7 and 10, Zhang, Mohtar et al., and Ruiz-Opazo et al. teach wherein said peptide is one of the following: - encapsulated into a liposome; - linked to or encapsulated into a nanoparticle; or - encapsulated into an extracellular vesicle. Ruiz-Opazo et al. is in the field of cancer research (see abstract), and specifically primary pancreatic cancer (PDAC) (see paragraph [0054] within Ruiz-Opazo et al.). Ruiz-Opazo et al. disclose polypeptides (see paragraphs [0081-0101] within Ruiz-Opazo et al.) that in some embodiments of any of the aspects, a pharmaceutically acceptable carrier can be a cream, emulsion, gel, liposome, nanoparticle, and/or ointment (see paragraph [0376] within Ruiz-Opazo et al.). Additionally, Ruiz-Opazo et al. disclose that in some embodiments of any of the aspects, an antibody, or antigen-binding portion thereof, and the chemotherapeutic agent can be present in a scaffold material. Scaffold materials suitable for use in therapeutic compositions are known in the art and can include, but are not limited to, a nanoparticle; a matrix; a hydrogel; and a biomaterial, biocompatible, and/or biodegradable scaffold material (such as poly(lactic-co-glycolic acid) [PLGA]) (see paragraph [0281] within Ruiz-Opazo et al.).
Therefore, a polypeptide and nanoparticle can be delivered simultaneously. A skilled artisan (POSITA) could use the teachings of Ruiz-Opazo et al. and apply them to the polypeptide of instant claim 1.
Regarding instant claims 8 and 21, Zhang, Mohtar et al., and Ruiz-Opazo et al. teach wherein - said peptide is encapsulated into a liposome, and wherein said liposome comprises a phospholipid selected from phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidic acid, phosphoinositides, phosphatidylinositol monophosphate, phosphatidylinositol bisphosphate, phosphatidylinositol triphosphate, ceramide phosphorylcholine, ceramide phosphorylethanolamine, ceramide phosphoryllipid and mixtures of any of the foregoing: or - wherein said peptide is linked to a nanoparticle, and wherein said nanoparticle is a solid nanoparticle; or - wherein said peptide is encapsulated into a nanoparticle and wherein said nanoparticle is a polymeric nanoparticle comprising a polymeric shell surrounding a core, wherein said shell comprises one or more of the following polymers: poly(lactic acid), poly(lactic-co-glycolic acid), chitosan, gelatin, poly-alkyl-acyanoacrylate, and mixtures of the foregoing, and said peptide is contained within said core of said polymeric nanoparticle; or - wherein said peptide is encapsulated into an extracellular vesicle.
Ruiz-Opazo et al. disclose polypeptides (see paragraphs [0081-0101] within Ruiz-Opazo et al.) can include a pharmaceutically acceptable carrier can be a cream, emulsion, gel, liposome, nanoparticle, and/or ointment (see paragraph [0376] within Ruiz-Opazo et al.). Therefore, a polypeptide and nanoparticle can be delivered simultaneously. [The Examiner has defined the term “linked” within instant claim 8 as meaning not covalently bonded to the nanoparticle.] Moreover, Ruiz-Opazo et al. disclose wherein the nanoparticle is an iron oxide-nanoparticle (IONP), polymeric nanoparticle, or gold nanoparticle, or chimeric nanoparticle (see claim 19 within Ruiz-Opazo et al.). Furthermore, Ruiz-Opazo et al. disclose that in some embodiments of any of the aspects, an antibody, or antigen-binding portion thereof, and the chemotherapeutic agent can be present in a scaffold material. Scaffold materials suitable for use in therapeutic compositions are known in the art and can include, but are not limited to, a nanoparticle; a matrix; a hydrogel; and a biomaterial, biocompatible, and/or biodegradable scaffold material (such as poly(lactic-co-glycolic acid) [PLGA]) (see paragraph [0281] within Ruiz-Opazo et al.).
Therefore, a skilled artisan (POSITA) could use the teachings of Ruiz-Opazo et al. and apply them to the polypeptide of instant claim 1.
Regarding instant claims 9 and 23, Zhang, Mohtar et al., and Ruiz-Opazo et al. teach wherein said liposome additionally comprises a sterol. Ruiz-Opazo et al. disclose that another modification of an inhibitory nucleic acid featured in the invention involves chemically linking to the inhibitory nucleic acid to one or more ligands, moieties or conjugates that enhance the activity, cellular distribution, pharmacokinetic properties, or cellular uptake of the iRNA. Such moieties include but are not limited to lipid moieties such as a cholesterol moiety (sterol) (see paragraph [0401] within Ruiz-Opazo et al.).
Thus, a skilled artisan (POSITA) could use the teachings of Ruiz-Opazo et al. and apply them to the polypeptide of instant claim 1.
Regarding instant claims 11, 12, and 25, Zhang, Mohtar et al., and Ruiz-Opazo et al. teach wherein said anti-cancer agent is selected from alkylating agents, platin analogues, intercalating agents, antibiotics, inhibitors of mitosis, taxoids, topoisomerase inhibitors, RNA polymerase inhibitors, and antimetabolites. Ruiz-Opazo et al. disclose the platin analogue, cisplatin (see paragraph [0314] within Ruiz-Opazo et al.). Ruiz-Opazo et al. also disclose alkylating agents, taxoids, anti-metabolites (5-floruracil), intercalating agents (daunorubicin), topoisomerase inhibitors, inhibitors of mitosis, and antibiotics (see paragraph [0314] within Ruiz-Opazo et al.).
Thus, a skilled artisan (POSITA) could use the teachings of Ruiz-Opazo et al. and apply them to the polypeptide of instant claim 1.
Regarding instant claim 24, Zhang, Mohtar et al., and Ruiz-Opazo et al. teach wherein said anti-cancer agent is coupled to an antibody, antibody fragment, a growth factor or growth factor receptor. Ruiz-Opazo et al. disclose where the antibody or antibody fragment is coupled to the anti-cancer agent (drug-antibody conjugate; see paragraph [0316] within Ruiz-Opazo et al.).
Thus, a skilled artisan (POSITA) could use the teachings of Ruiz-Opazo et al. and apply them to the polypeptide of instant claim 1.
Combination of Zhang, Mohtar et al., and Kondo et al.
Regarding instant claim 22, Zhang, Mohtar et al., and Kondo et al. teach wherein said peptide is encapsulated into an extracellular vesicle which is an exosome. Kondo et al. is in the field of cancer research with polypeptides (see title and abstract within Kondo et al.). Kondo et al. disclose that the peptide of an embodiment of the present invention can be used in a form bonded to the expression of a liposome, virus, exosome or polymer micelle, a form in which either one, or a plurality of two or more of the peptides are bonded to the side-chain portion of a dendrimer, or a form in which an antibody (immunoglobulin) and the peptide are bonded together (see paragraph [0132] within Kondo et al.). In this manner, the exosome encapsulates the polypeptide.
Therefore, a skilled artisan (POSITA) could use the teachings of Kondo et al. and apply them to the polypeptide of instant claim 1.
In the context of instant method claims 16-20, the desired purpose defines an effect that arises from, and is implicit in the method step(s). Thus, where the purpose is limited to stating a technical effect that inevitably occurs during the performance of the claimed method step(s), and is therefore inherent in that/those step(s), that technical effect is not limiting to the subject-matter of the claim. Thus, the present method claims, defining the application/use of the composition according to the previous instant claims and defining its purpose as "use", is anticipated by any document of the state of the art describing a method of using the composition.
Analogous Art
The Zhang, Mohtar et al., Ruiz-Opazo et al., Kentsis et al., and Kondo et al. references are directly relevant to the endeavor of the instant application. Zhang, Mohtar et al., Ruiz-Opazo et al., Kentsis et al., and Kondo et al. in combination teach all the elements of instant claims 1-12 and 16-25.
Obviousness
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the polypeptide having a NTAIYY sequence disclosed by Zhang, using the teachings of Mohtar et al., Ruiz-Opazo et al., Kentsis et al., and Kondo et al. to incorporate the necessary claim limitations. Starting with Zhang, the skilled person only had to try the addition of the necessary claim limitations disclosed by Mohtar et al., Ruiz-Opazo et al., Kentsis et al., and Kondo et al. The combination of Zhang, Mohtar et al., Ruiz-Opazo et al., Kentsis et al., and Kondo et al. would allow one to arrive at the present application without employing inventive skill. This combination of the polypeptide having a NTAIYY sequence taught by Zhang along with the use of the necessary claim limitations taught by Mohtar et al., Ruiz-Opazo et al., Kentsis et al., and Kondo et al., would allow a research and development scientist (POSITA) to develop the invention taught in the instant application. It would have only required routine experimentation to modify the polypeptide having a NTAIYY sequence disclosed by Zhang with the use of the necessary claim limitations taught by Mohtar et al., Ruiz-Opazo et al., Kentsis et al., and Kondo et al. This combined modification would have led to an enhanced polypeptide having a NTAIYY sequence that would be beneficial for patients.
Response to Arguments
Applicant's arguments filed August 13, 2025 have been fully considered but they are not persuasive.
The Applicant’s claim amendments were sufficient to address the claim objections, 35 U.S.C. §112(a) rejection, and 35 U.S.C. §102 rejections. Therefore, the claim objections, 35 U.S.C. §112(a) rejection, and 35 U.S.C. §102 rejections from the Non-Final office action dated May 16, 2025 are withdrawn.
The Applicant’s claim amendments did not necessitate a new ground of rejection.
Applicant Argument: The Applicant argues that the instant claim amendment to claim 1 removes any anticipation rejection.
Examiner’s Rebuttal: The Examiner submits that the instant claim 1 amendment was sufficient to withdraw the 35 U.S.C. §102 rejections from the nonfinal office action. [Since both the Genbank and RPB1_Human rejections have been withdrawn the Examiner will remove these references from the remaining arguments.]
However, the Examiner has constructed a 35 U.S.C. §103 rejection using the Zhang reference as the primary citation. Zhang discloses the hexapeptide NTAIYY:
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Zhang discloses wherein said peptide is a hexapeptide. Zhang discloses the Polr2a protein sequence that binds to Agr2 (aa 1173-1177), TAIYY (see page 60 within Zhang). Moreover, the residue at position 1172 is N [SEQ ID NO:2]
Furthermore, the secondary reference Mohtar et al. disclose that peptide A4 with the sequence HLPTTIYYGPPG (containing the key functional pentapeptide
sequence italicized) [partial SEQ ID NO:3] was previously shown to bind Agr2 (see page 742, 1st paragraph; and abstract; both within Mohtar et al.).
Therefore, a skilled artisan (POSITA) would be able to identify either hexapeptide NTAIYY or NTTIYY, which would be synthesized under routine experimental conditions and then biologically evaluated using the combined teachings of both Zhang and Mohtar et al.
Applicant Argument: The Applicant argues that there is no motivation to combine Zhang, Mohtar et al., Ruiz-Opazo et al., Kentsis et al., and Kondo et al.
Examiner’s Rebuttal: The Examiner respectfully disagrees. The motivation to combine the primary and secondary references Zhang and Mohtar et al. relies on the considerable overlap in background as it pertains to the protein sulfide isomerase AGR2. A skilled artisan (POSITA) would consult these references. Motivation to add the Ruiz-Opazo et al., Kentsis et al., and the Kondo et al. citations is to further support the primary and secondary references thereby addressing the claim limitations. The Ruiz-Opazo et al., Kentsis et al., and the Kondo et al. references all focus on therapeutic peptides for the treatment of (pancreatic) cancer.
Therefore, all references are analogous art and are suitable references due to there applicability to the instant application.
[In order to address the Applicant’s future argument that the Examiner's conclusion of obviousness is based upon improper hindsight reasoning the following rebuttal is made. 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).]
Applicant Argument: The Applicant argues that the Zhang disclosure makes reference to a statement that suggests caution regarding the pursuit of Agr2 inhibitors.
Examiner’s Rebuttal: The Examiner respectfully disagrees. Zhang teaches on page 73 that:
Question 4: What is the potential application of Agr2-based interference in pancreatic cancer?
Conclusion 4: Since Agr2 plays an essential role in pancreatic carcinogenesis, the application of Agr2 inhibitors (antibodies, peptide, siRNA) would be carried out with caution. In this study, we showed that Agr2 knockdown sensitizes PDAC cell lines and patient-derived PDAC cell lines with wild-type p53 to a specific Pol II inhibitor: ɑ-Amanitin. Thus, Agr2-based treatment needed further investigation.
The Examiner points specifically to the last underlined phrase, “Agr2-based treatment needed further investigation.” Zhang is not suggesting to move forward in research and development. Just to further investigate the potential of Agr2 inhibitors. This is exactly what a skilled artisan (POSITA) would accomplish by synthesizing and evaluating the hexapeptide, either NTAIYY or NTTIYY.
Applicant Argument: The Applicant argues that the Zhang, Mohtar et al., Ruiz-Opazo et al., Kentsis et al., and Kondo et al. references fail to teach or suggest the claimed invention.
Examiner’s Rebuttal: The Examiner respectfully disagrees. The above rebuttal discussing the motivation to combine the references provides the necessary statements to allow a skilled artisan (POSITA) to use the disclosed citations. Thus, the instant application is prima facie obvious based on the references of record. All claim limitations are disclosed by the citations.
Therefore, the 35 U.S.C. § 103 rejection is maintained for instant claims 1-12 and 16-25.
Conclusion
No claims are allowed.
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.
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/JOHN W LIPPERT III/Examiner, Art Unit 1615 /Robert A Wax/Supervisory Patent Examiner, Art Unit 1615