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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 4/18/25 has been entered.
Election/Restrictions
For the record, applicant on 12/28/23 elected as follows:
Applicant’s election without traverse of Group I, drawn to peptides according to claims 1-4 in the reply filed on 12/28/23 is acknowledged.
Applicant’s election without traverse of “the peptide comprising the species as set forth in SEQ ID NO:5” in the reply filed on 12/28/23 is acknowledged.
Claims 5-7 and 9-23 were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/28/2023.
Priority
The instant application, filed 07/06/2021 and having 1 RCE-type filing therein is a National Stage entry of PCT/US2020/012323 , International Filing Date: 01/06/2020
PCT/US2020/012323 Claims Priority from Provisional Application 62789114 , filed 01/07/2019.
Status of the Claims
Claim(s) 1-8 and 24-29 are pending.
Claims 9-23 are cancelled
Claims 5-7 and 9-23 were withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/28/2023.
New claims 27-29 are withdrawn based on depending from withdrawn claim 5.
Claims 1-4, 8 and 24-26 are hereby examined on the merits.
Election of Species Practice
The prior art search will not be extended unnecessarily to cover all nonelected species. Should applicant, in response to this rejection of the Markush-type claim, overcome the rejection, as by amending the Markush-type claim to exclude the species anticipated or rendered obvious by the prior art, the amended Markush-type claim will be reexamined. The examination will be extended to the extent necessary to determine patentability of the Markush-type claim. In the event prior art is found during the reexamination that anticipates or renders obvious the amended Markush-type claim, the claim will be rejected and the action can be made final unless the examiner introduces a new ground of rejection that is neither necessitated by applicant’s amendment of the claims nor based on information submitted in an information disclosure statement filed during the period set forth in 37 CFR 1.97(c) with the fee set forth in 37 CFR 1.17(p). See MPEP § 706.07(a). Amendments submitted after the final rejection further restricting the scope of the claim may be denied entry if they do not comply with the requirements of 37 CFR 1.116. See MPEP § 714.13.
The elected species has not been found free of the prior art. The search has been extended as indicated above to the next species that is found in Claims 1-4 given that the peptides have the same primary sequence but differ only in the N- and C- terminal modification and/or chirality of the amino acids. That or those species have not been found free of the prior art. There is no allowable subject matter.
Information Disclosure Statement
The Examiner has considered the reference(s) provided in the 4/18/25 Information Disclosure Statement, and provides a signed and dated copy of such herewith.
Interview Summary
A telephonic interview was conducted and an Interview Summary is provided herewith.
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, 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(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.
For the purpose of this invention, the level of ordinary skill in the art is deemed to be at least that level of skill demonstrated by the patents in the relevant art. Joy Technologies Inc. V. Quigg, 14 USPQ2d 1432 (DC 1990).
One of ordinary skill in the art is held in accountable not only for specific teachings of references, but also for inferences which those skilled in the art may reasonably be expected to draw. In re Hoeschele, 160 USPQ 809, 811 (CCPA 1969).
In addition, one of ordinary skill in the art is motivated by economics to depart from the prior art to reduce costs consistent with desired product properties. In re Clinton, 188 USPQ 365, 367 (CCPA 1976);In re Thompson, 192 USPQ 275, 277 (CCPA 1976).
Claims 1-4, 8 and 24-26 are rejected under 35 U.S.C. 103 as being unpatentable over Dewji (Applicant), US 8,129,334 (corresponding PGPUB US 2009/0305946), in view of “Strategic Approaches to Optimizing Peptide ADME Properties,” Li Di, The AAPS Journal, Vol. 17, No. 1, January 2015, pp 134-143 (“Di”) and “A D‑Amino Acid at the N‑Terminus of a Protein Abrogates Its Degradation by the N‑End Rule Pathway,” authors Rabideau and Pentelute, ACS Cent. Sci. 2015, 1, 423−430 (“RP”).
The instant invention of claim 1, the sole independent claim, is drawn to
a sequence of Ac-DEEEDEEL-NH2 (SEQ ID NO:3), wherein the N-terminal amino acid Asp (D) is acetylated and the C-terminal amino acid Leu is amidated;
(ii) a sequence of dEEEDEEL-NH2 (SEQ ID NO:4), wherein the N-terminal amino acid Asp (D) is a D-amino acid and the C-terminal amino acid Leu is amidated; or
(iii) a sequence of Ac-dEEEDEEL-NH2 (SEQ ID NO:5), wherein the N-terminal amino acid Asp (D) is a D-amino acid and is acetylated and the C-terminal amino acid Leu is amidated.
Claims depending from claim 1 narrow the selection to one of the claim 1 sequences, including in pharmaceutical compositions.1
Dewji teaches the sequence N-DEEEDEEL-COOH, SEQ ID NO:5 as an isolated peptide that functions as an interfering agent for inhibiting production of Aβ, columns 3 and 4, at col. 3 lines 34-39 in one embodiment the isolated peptide consists essentially of N-DEEEDEEL-COOH (SEQ ID NO:5), followed by an alternative genus that adds up to 50 amino acids at either end. SEQ ID NO:5 also is found in claim 1 and elsewhere in the specification, shown in these locations as well as in the sequence listing as DEEEDEEL, so indicating the N-terminus N is the amino of the aspartic acid, and the COOH is the carboxylic acid group of the C-terminus leucine.
As to the performance of this sequence in reducing or inhibiting production of Aβ, this sequence, identified in Figure 26 as Peptide 8 (see col. 9, lines 48-58), was among two peptides that were most effective:
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It is noted that Peptide 7, DEEEDEELTLKYGAK (SEQ ID NO:17), although performing similarly to SEQ ID NO:5 (identified as Peptide 8), did not appear to indicate a benefit from having the additional TLKYGAK amino acids to the C-terminus of the core 8-mer of SEQ ID NO:5 (underlined in SEQ ID NO:17).
The superior performance of SEQ ID NO:5, identified in Figure 26 as Peptide 8, would suggest to one of ordinary skill in the art that this peptide is a very good candidate for further modification to improve its effectiveness and performance. That is, one of ordinary skill in the art appreciating this superior performance would reasonably be motivated to improve this peptide by a number of peptide improvement approaches known to those of ordinary skill in the art.
In this regard, Dewji further generally teaches, after listing alternative embodiments of its peptides including but not limited to N-DEEEDEEL-COOH (SEQ ID NO:5) and additions thereto, “any of the foregoing comprising an unnatural amino acid or D-amino acid wherein the peptide inhibits cell-cell interaction, inhibits A.beta. production or binds to a .beta.-APP,” para 18 of the PGPUB ‘946.
Dewji further teaches that “Additional variants within the scope of the disclosure include polypeptides that can be modified to create derivatives thereof by forming covalent or aggregative conjugates with other chemical moieties, such as glycosyl groups, lipids, phosphate, acetyl groups and the like,” para 80 of the PGPUB ‘946.
Dewji teaches pharmaceutical compositions comprising agents for the treatment of an amyloid-related disease, as well as methods of manufacturing such pharmaceutical compositions, para 138, see also paras 139-151, of the PGPUB ‘946.
Dewji teaches that its pharmaceutical compositions that include its peptide also comprise a pharmaceutically acceptable excipient, see paras 139-151 and particularly para 146 of the PGPUB ‘946.
The difference between what is taught by the prior art and that instantly claimed is that while Dewji teaches and claims and demonstrates in Figure 26 superior effect of the same peptide sequence having the same length, Dewji does not explicitly teach the N- and C-terminus modifications particularly for its SEQ ID NO:5 that are found in instantly claimed SEQ ID NO: 3, 4, and 5. Note that SEQ ID NO:5 of the instant case and the prior art case are the same amino acid sequence and differ from Dewji’s SEQ ID NO:5 by their respective N- and C-terminus modifications, and the same is true for instantly claimed SEQ ID Nos: 3 and 4, that is, the amino acid sequences are the same other than a substitution of a D-form aspartic acid for standard, L-form aspartic acid in instant SEQ ID NOs: 4 and 5.
However, the additional references clearly teach that the modifications made are well known in the art and routinely applied to improve one or more pharmacological characteristics.
Di teaches that a routine approach to optimizing peptides, with regard to improved absorption, distribution, metabolism and excretion (ADME) properties is to acylate the N-terminus and amidate the C-terminus, page 137 stating in part, “A number of proteolytic enzymes in blood/plasma, liver or kidney are exopeptidases, aminopeptidases and carboxypeptidases and they break down peptide sequences from the N- and C-termini. Modification of the N- or/and C-termini can often improve peptide stability. Many examples have reported that N-acetylation, and C-amidation increase resistance to proteolysis (8,76).” Specific examples of improved stability follow this general approach statement.
On the same page Di teaches broadly, “Substituting natural L-amino acids with nonnatural D-amino acids decreases the substrate recognition and binding affinity of proteolytic enzymes and increases stability,” however the examples include changing all L-amino acids with D-amino acids, which is not the case here.
More explicitly, specifically, and of greater relevance, RP teaches that “A D‑Amino Acid at the N‑Terminus of a Protein Abrogates Its Degradation by the N‑End Rule Pathway,” this being the title and also the key point of the article. In summarizing their studies, RP states, “In all cases, we observed that one N-terminal D-amino acid stabilized the cargo protein to proteasomal degradation with respect to the N-end rule. We found that since the mixed chirality proteins were not polyubiquitinated, they evaded N-end-mediated proteasomal degradation. Evidently, a subtle change on the N-terminus of a natural protein can enhance its intracellular lifetime.”
Di and RP teach the modifications that are found in instant SEQ ID Nos: 3-5 relative to Dewji’s favored SEQ ID NO:5 peptide.
One of ordinary skill in the art, motivated to improve stability and other pharmacological properties of the SEQ ID NO:5 peptide of Dewji, which per above is taught and suggested in Dewji to be included in a pharmaceutical composition with a pharmaceutically acceptable excipient, would reasonably have been motivated to modify SEQ ID NO:5 by 1) at the N-terminus acylating [as in instant SEQ ID NO:3 peptide] or modifying the N-terminus aspartic acid to a D-form aspartic acid [as in instant SEQ ID NO:4 peptide], or both [as in instant SEQ ID NO:5 peptide], and 2) at the C-terminus amidating the C-terminus leucine [as in all of instant SEQ ID NOS: 3-5]. The rationale is to apply known techniques to known products that are ready for improvement, in order to improve their performance properties, here including increased stability in vivo as well as in vitro with proteases present, to yield predictable results. There would have been a reasonable expectation of success based on the clear teachings of Di and RP as to known effects and improvements.
Additionally, the strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In re Sernaker, 702 F.2d 989, 994-95, 217 USPQ 1, 5-6 (Fed. Cir. 1983). Here the reasonably expected advantages are increased stabilities.
Based on the above, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, based on the combined teachings and suggestions of the references.
Accordingly, claims 1-4, 8 and 26-28 are rejected as obvious.
Response to Arguments and Consideration of Assertions of Unexpected Results
Applicant's arguments filed 4/18/25 have been fully considered but they are not persuasive.
This section includes the examiner’s response to assertions of unexpected results, including assertions made by attorney’s during a telephonic interview, and as considered then and subsequently by the examiner.
The current rationale for combining the references’ teachings and suggestions does not include obvious to try, so arguments against this on page 6 are moot.
As to “more than predictable results” statements of the law on page 6, and allegedly unpredictable results, the examiner has provided references that broadly teach the advantages of N-terminal acetylation, C-terminal amidation, and d-amino acid modification of the N-terminus amino acid. Absolute predictability is not required, see MPEP 2143.02 in its entirety.
Additionally, the examiner notes that applicant’s representatives have explained the data of the application, see Interview Summary provided, arguing and asserting unexpected results, and the examiner has considered this thoroughly, but given the nature of the data and the expectation from the references that the N-terminal acetylation, C-terminal amidation, and d-amino acid modification of the N-terminus amino acid would reasonably improve stability, at least when in the blood stream and also when in cells, the examiner is not persuaded that the data conclusively demonstrates unexpected results.
The motivation to combine arguments starting on page 7 are moot because different secondary references are provided in the instant rejection. Further as to the excerpts regarding very small changes can have dramatic effects, while this is true its broad application would obviate being able to make reasonable obviousness rejections that are based on combining teachings and methods known in the art to make improvements using approaches generally known and reasonably expected to provide an improved product or method.
With regard to concerns about aggregation and Exhibit A, the peptides as claimed are not at any claimed concentration that could indicate an advantage with regard to aggregation, and the results are easily attributed to improvements in stability reasonably expected as a result of the N- and C-terminus modifications when considering the secondary references. The RP reference is much more specific and narrow versus the general combining of “incorporation of non-natural amino acids, into the peptides, engineering of disulfide bonds into the peptides, and lipidation or acylation of the peptide,” the examiner further noting that as used in this quote acylation is not restricted to just an acetyl at the N-terminus.
As to page 8’s “Specifications teach. Claims claim,” the rejection above provides motivation from the Dewji specification/data to focus on its SEQ ID NO:5 for further improvement using methods known in the art.
Grasso as well as Smith I, Smith II and Peers are no longer applied so argument against one or more of these are moot.
Regarding pages 12-14, as above the examiner has considered the assertions and data regarding unexpected results and concluded that he has not found the results in the application to rise to the level of unexpected. Greater in vivo stability of the peptides having the N- and C-termini modifications that reasonably would improve that stability would reasonably lead to an increase in the number of peptide molecules able to cross the BBB from IV or SC administrations, this based on less protease-based and other degradation as a result of those modifications. Applicant’s data does not parse the expected effects – improvements in stability as a result of less degradation by proteases and per RP from proteosomes, from any difference that can reasonably rise to be surprising and/or unexpected. Stated another way, if the unmodified control peptide P8 is substantially broken down by the proteases that the modifications protect against, one would reasonably expect less of P8 to arrive at the BBB and to cross into the CSF. Similarly, once in the CSF, one would reasonably expect that the P8 peptide, lacking protections at its N- and C-termini, and lacking an N-terminus D-aspartic acid, would degrade more rapidly than peptides having the same sequence but protections at their N- and C-termini and/or N-terminus D-aspartic acid. Based on these considerations, the examiner considers that the differences that the examiner perceives in the data of the tables and figures is not unexpected based on reasonably expected less degradation and consequent improvements in stability. The examiner is not arguing that the closest prior art for comparison is what the invention is, see MPEP 716.02(e) III, but that one of ordinary skill in the art at the time of applicant’s invention reasonably would expect improved stability, and consequent greater activity, by employing the modifications taught by the secondary references when implemented to the peptide of SEQ ID NO:5 of Dewji. The issue of whether the amount of improvement shown in the figures arises to the level of unexpected results beyond that which is reasonably expected from the implementing the known in the art N- and C-termini improvements has not been persuasively demonstrated at least in part based on limitations of the data underlying the figures, some confusing information in the figures/specification, and a lack of relevant controls.
Applicant is encouraged to provide data that more definitively sets forth clear results that more persuasively indicate surprising and/or unexpected results when compared to suitable controls and other treatments as applicant considers relevant and appropriate. Please see relevant MPEP sections.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4, 8 and 24-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 8129334 (Reference patent, also “Dewji”) in view of US 20120214235, Dewji and Singer, published 8/23/12 (‘235), “Strategic Approaches to Optimizing Peptide ADME Properties,” Li Di, The AAPS Journal, Vol. 17, No. 1, January 2015, pp 134-143 (“Di”) and “A D‑Amino Acid at the N‑Terminus of a Protein Abrogates Its Degradation by the N‑End Rule Pathway,” authors Rabideau and Pentelute, ACS Cent. Sci. 2015, 1, 423−430 (“RP”).
The instant invention of claim 1, the sole independent claim, is drawn to
(i) a sequence of Ac-DEEEDEEL-NH2 (SEQ ID NO:3), wherein the N-terminal amino acid Asp (D) is acetylated and the C-terminal amino acid Leu is amidated;
(ii) (ii) a sequence of dEEEDEEL-NH2 (SEQ ID NO:4), wherein the N-terminal amino acid Asp (D) is a D-amino acid and the C-terminal amino acid Leu is amidated; or
(iii) (iii) a sequence of Ac-dEEEDEEL-NH2 (SEQ ID NO:5), wherein the N-terminal amino acid Asp (D) is a D-amino acid and is acetylated and the C-terminal amino acid Leu is amidated.
Claims depending from claim 1 narrow the selection to one of the claim 1 sequences, including in pharmaceutical compositions.
Dewji claim 1 claims an isolated polypeptide consisting essentially of a fragment of an N-terminal domain of a Presenilin-1 polypeptide, said domain having a sequence from amino acid x.sub.1 to x.sub.2 of SEQ ID NO:2, wherein x.sub.1 is selected from amino acid 1, 2, 3, 4, and 5 of SEQ ID NO:2 and x.sub.2 is selected from amino acid 79, 80, 81, 82 and 83 of SEQ ID NO:2 wherein the isolated polypeptide contains an amino acid sequence selected from the group consisting of: (i) DEEEDEEL (SEQ ID NO:5), and other alternatives some of which also include DEEEDEEL. This repeated focus on DEEEDEEL suggests to one of ordinary skill in the art that this is an important peptide sequence for further improvement, and would suggest to one of ordinary skill in the art that this peptide is a very good candidate for further modification to improve its effectiveness and performance.
This importance of DEEDEEL is additionally supported by the teachings of the ‘235 publication, at least because this sequence, identified in Figure 26 as Peptide 8, was among two peptides that were most effective:
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It is noted that Peptide 7, DEEEDEELTLKYGAK (SEQ ID NO:17), although performing similarly to SEQ ID NO:5 (identified as Peptide 8), did not appear to indicate a benefit from having the additional TLKYGAK amino acids to the C-terminus of the core 8-mer of SEQ ID NO:5 (underlined in SEQ ID NO:17).
The superior performance of SEQ ID NO:5, identified in Figure 26 as Peptide 8, would suggest to one of ordinary skill in the art that this peptide is a very good candidate for further modification to improve its effectiveness and performance. That is, one of ordinary skill in the art appreciating this superior performance would reasonably be motivated to improve this peptide by a number of peptide improvement approaches known to those of ordinary skill in the art. The ‘235 SEQ ID NO:5 is identical to the Dewji claim 1 SEQ ID NO:5
The ’235 further generally teaches, after listing alternative embodiments of its peptides including but not limited to N-DEEEDEEL-COOH (SEQ ID NO:5) and additions thereto, “any of the foregoing comprising an unnatural amino acid or D-amino acid wherein the peptide inhibits cell-cell interaction, inhibits A.beta. production or binds to a .beta.-APP,” para 22.
The ‘235 further teaches that “Additional variants within the scope of the disclosure include polypeptides that can be modified to create derivatives thereof by forming covalent or aggregative conjugates with other chemical moieties, such as glycosyl groups, lipids, phosphate, acetyl groups and the like,” para 79.
The ‘235 teaches pharmaceutical compositions comprising agents for the treatment of an amyloid-related disease, as well as methods of manufacturing such pharmaceutical compositions, para 138, see also paras 139-151.
The ‘235 teaches that its pharmaceutical compositions that include its peptide also comprise a pharmaceutically acceptable excipient, see paras 139-151 and particularly para 146.
One of ordinary skill in the art appreciating this superior performance would reasonably be motivated to improve this peptide by a number of peptide improvement approaches known to those of ordinary skill in the art.
In this regard, the ‘235 also further generally teaches, after listing alternative embodiments of its peptides including but not limited to N-DEEEDEEL-COOH (SEQ ID NO:5) and additions thereto, “any of the foregoing comprising an unnatural amino acid or D-amino acid wherein the peptide inhibits cell-cell interaction, inhibits A.beta. production or binds to a .beta.-APP,” para 22.
The ‘235 further teaches that “Additional variants within the scope of the disclosure include polypeptides that can be modified to create derivatives thereof by forming covalent or aggregative conjugates with other chemical moieties, such as glycosyl groups, lipids, phosphate, acetyl groups and the like,” para 80.
The difference between what is taught by the prior art and that instantly claimed is that while Dewji claims an isolated peptide DEEEDEEL, Dewji does not explicitly claim this with the N- and C-terminus modifications particularly for its SEQ ID NO:5 that are found in instantly claimed SEQ ID NO: 3, 4, and 5. Note that SEQ ID NO:5 of the instant case and Dewji claim 1 are the same amino acid sequence and differ from Dewji’s claim 1 SEQ ID NO:5 by their respective N- and C-terminus modifications, and the same is true for instantly claimed SEQ ID Nos: 3 and 4, that is, the amino acid sequences are the same other than a substitution of a D-form aspartic acid in instant SEQ ID NOs: 4 and 5.
The additional references clearly teach that the modifications made are well known in the art and routinely applied to improve one or more pharmacological characteristics.
Di teaches that a routine approach to optimizing peptides, with regard to improved absorption, distribution, metabolism and excretion (ADME) properties is to acylate the N-terminus and amidate the C-terminus, page 137 stating in part, “A number of proteolytic enzymes in blood/plasma, liver or kidney are exopeptidases, aminopeptidases and carboxypeptidases and they break down peptide sequences from the N- and C-termini. Modification of the N- or/and C-termini can often improve peptide stability. Many examples have reported that N-acetylation, and C-amidation increase resistance to proteolysis (8,76).” Specific examples of improved stability follow this general approach statement.
On the same page Di teaches broadly, “Substituting natural L-amino acids with nonnatural D-amino acids decreases the substrate recognition and binding affinity of proteolytic enzymes and increases stability,” however the examples include changing all L-amino acids with D-amino acids, which is not the case here.
More explicitly, specifically, and of greater relevance, RP teaches that “A D‑Amino Acid at the N‑Terminus of a Protein Abrogates Its Degradation by the N‑End Rule Pathway,” this being the title and also the key point of the article. In summarizing their studies, RP states, “In all cases, we observed that one N-terminal D-amino acid stabilized the cargo protein to proteasomal degradation with respect to the N-end rule. We found that since the mixed chirality proteins were not polyubiquitinated, they evaded N-end-mediated proteasomal degradation. Evidently, a subtle change on the N-terminus of a natural protein can enhance its intracellular lifetime.”
Di and RP teach the modifications that are found in instant SEQ ID Nos: 3-5 relative to Dewji’s SEQ ID NO:5 peptide of its claim 1.
One of ordinary skill in the art, motivated to improve stability and other pharmacological properties of the SEQ ID NO:5 peptide of Dewji claim 1, which per above is taught and suggested in the ‘235 to be included in a pharmaceutical composition with a pharmaceutically acceptable excipient, would reasonably have been motivated to modify SEQ ID NO:5 by 1) at the N-terminus acylating [as in instant SEQ ID NO:3 peptide] or modifying the N-terminus aspartic acid to a D-form aspartic acid [as in instant SEQ ID NO:4 peptide], or both [as in instant SEQ ID NO:5 peptide], and 2) at the C-terminus amidating the C-terminus leucine [as in all of instant SEQ ID NOS: 3-5]. The rationale is to apply known techniques to known products that are ready for improvement, in order to improve their performance properties, here including increased stability in vivo as well as in vitro with proteases present, to yield predictable results. There would have been a reasonable expectation of success based on the clear teachings of Di and RP as to known effects and improvements.
Additionally, the strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In re Sernaker, 702 F.2d 989, 994-95, 217 USPQ 1, 5-6 (Fed. Cir. 1983). Here the reasonably expected advantages are increased stabilities.
Based on the above, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, based on the Reference patent (Dewji) claim 1 and the combined teachings and suggestions of the applied secondary references.
Accordingly, claims 1-4, 8 and 24-26 are rejected under this section.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH FISCHER whose telephone number is (571)270-7925, and whose direct facsimile number is (571)270-8925. The examiner can normally be reached on Monday to Friday, 9:00 AM to 5:00 PM, however noting that the examiner will not normally be working on Monday/Tuesday and on Wednesday-Friday on alternating weeks, but will promptly answer messages upon his return to work.
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/Joseph Fischer/
Examiner, Art Unit 1658
1 The examiner observes that given the open transition comprising in claim 1, “A peptide comprising … a sequence of dEEEEDEEL-NH2 (SEQ ID NO:4)” can include additional amino acids extending from the SEQ ID NO:4 N-terminus D-form aspartic acid. The instant rejection focuses on the peptide sequence of dEEEEDEEL without any such additional amino acids, in that this is what was evaluated and what the examiner believes has been emphasized by attorneys for applicant during the telephonic interview.