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 .
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 of RCE on March 26, 2026 and amendment after final filed on March 26, 2026 has been entered. Claims 2, 16-17, 19 were canceled, claims 1 and 5 were amended and claims 1, 3-15, 18, 20-22 are pending in the instant application.
The was restriction deemed proper and made FINAL in the previous office action. Claims 4, 6-15, 20-22 remain withdrawn as being drawn to a non-elected species/invention. Claims 1, 3, 5 and 18 examined on the merits of this office action.
In the prior final office action mailed November 26, 2025, claim 18 was indicated as containing allowable subject matter. Upon further consideration of the prior art and in view of newly applied references below, the Examiner has determined that claim 18 is unpatentable under 35 U.S.C. 103. Accordingly, claim 18 is now rejected as set forth below.
Withdrawn Objections
The objection to claims 1 and 5 are withdrawn in view of amendment of the claims filed February 25, 2026.
Declaration under 37 C.F.R 1.132
The Declaration under 37 CFR 1.132 filed March 26, 2026 is insufficient to overcome the rejection of Claim(s) 1, 3 and 5 based upon rejection under 35 U.S.C. 103 as being unpatentable over Cheng (US20150284430 A1, cited previously) in view of Liftein (https://www.lifetein.com/Peptide-Synthesis-D-Amino-Acid.html, online 2014, cited previously). as set forth in the last Office action because: Applicants argue that SIPI-D000 has improved metabolic stability. In particular, Applicants conclude that after 60 minutes, there is .67% SP (reverse sequence of Cheng without D-amino acids) remaining and a 10.4 min half-life and 103% of SIPI-D00 remaining with a 1.05 hr half life (the retroinverso of the peptide of Cheng). Applicants arguments have been fully considered but not found persuasive. The demonstrated improvements in metabolic stability, half life and exposure are fully consistent with and expected from L-amino acid substitution with D-amino acids and formation of retro inverso peptides, as taught by Lifetein. Such modifications are well known to confer protease resistance and prolonged systemic exposure, and therefore do not constitute evidence of non-obviousness.
Applicants argue that SIPI-D00 has higher binding affinity to CD81. In particular, SIPI-D00 has 10 fold stronger binding as compared to SP. Applicants arguments have been fully considered but not found persuasive. While the declaration shows 10 fold increased affinity, the improved binding affinity is a predictable consequence of enhanced stability and prolonged exposure. Furthermore, there is no comparison with the closest prior art (Cheng). MPEP 716.02(e) states “An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). "A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference." In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960) (deviations from example were inconsequential).
Applicants argue SIPI-D00 shows superior in vivo efficacy. Applicants provide OVA-induced asthma model and treatment with SIPI-D00 and SP. Applicants found SIPI-D00 reduced airway resistance, increased lung compliance and decreased eosinophils and inflammatory cells. SP had no statistically significant improvement. Applicants arguments have been fully considered. As stated above, the comparison is made to the SP peptide, not the peptide of the closest prior art of Cheng (see MPEP 716.02 (e)). Furthermore, the improved efficacy is reasonably explained by increased stability and bioavailability both of which can be contributed to retro inversion and including D-amino acids as these are known expected benefits. The data show improved degree of performance (stability driven efficacy), not a new function or an effect contrary to expectation as compared to the peptide of the closest prior art. Moreover, the declaration does not sufficiently demonstrate that lack of observed efficacy for SP is due to intrinsic inactivity rather than rapid degradation or insufficient exposure.
Applicants argue that the effect is not due to stability alone and this is seen with the higher CD81 affinity and biological activity differences. Overall Applicant’s argue that SIPI-D00 has better stability, better binding and better efficacy. Applicants arguments have been fully considered. The declaration does not provided evidence separating the effects of stability from intrinsic binding differences and there is not comparison to the peptide of the prior art. The increased affinity itself may be a downstream consequence of improved stability as stated above due to expected differences of creating retro inverso peptides and peptides with D-amino acids.
Furthermore, the evidence provided in the declaration is not commensurate in scope with the claimed invention. The data are limited to a single peptide species, SIPI-D00, evaluated under specific experimental conditions. However, the claims encompass a broader genus of peptides, including slight variation in amino acid sequence (truncation or any amino acid at the terminal ends) and the extent and position of D-amino acid substitutions. The declaration does not provide sufficient evidence that the alleged improvements in binding affinity or in vivo efficacy would be exhibited across the full scope of the claimed peptides. Accordingly, even if the results for SIPI-D00 were considered favorable, they are not sufficient to establish non obviousness for the full breadth of the claims.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Maintained/Revised Rejections
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 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.
Claim(s) 1, 3 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Cheng (US20150284430 A1, cited previously) in view of Liftein (https://www.lifetein.com/Peptide-Synthesis-D-Amino-Acid.html, online 2014, cited previously).
Cheng teaches a method of treating asthma comprising administering the peptide GQTYTSG (see claims 1-2). Regarding claim 5, Cheng teaches administering the peptide in combination with a pharmaceutically acceptable carrier (see paragraph 0022).
The peptide of Cheng is the reverse sequence of instant SEQ ID NO:2. Cheng does not teach the sequence of instant SEQ ID NO:2 and all d-amino acids.
However, Liftein teaches “Retro-inverso peptides are composed of D-amino acids that are assembled in the reverse order of their parental L-sequences. Retro-inverso peptides are obtained by replacing the normal L-amino acid residues with the corresponding D-amino acids and reversing the direction of the peptide backbone. Therefore, the original spatial orientation and the chirality of the side chains is unchanged. This results in a non-complementary side chain topochemistry between the analog and the parental L-peptide. Advantages of retro-inverso peptides: Retention of protein bioactivity, Long-lasting proteolytic stability in vivo and Antigenic mimicry of natural L-peptides” (See page 2). D-amino acids are more resistant to proteases (see pages 3-4) which in turn prolongs activity.
It would have been obvious before the effective filing date of the claimed invention to create a retro-inverso analog of the peptide of Cheng. One of ordinary skill the in art would have been motivated to do so to create a more stable peptide with long lasting proteolytic stability in vivo and retained protein bioactivity for a longer period of time. There is a reasonable expectation of success given enhanced proteolytic stability and retained bioactivity are desired properties for therapeutic agents.
Regarding claim 3, the retro-inverso sequence of SEQ ID NO:2 of Cheng results in a peptide comprising SEQ ID NO:2 with all D-amino acids thus meeting the limitations of instant claim 3.
Response to Applicant’s Augments
The following are the arguments provided in the response filed February 25, 2026. Applicants argue that the claimed peptide SIPI-D00 (SEQ ID NO:2) exhibits unexpected properties relative to the SP peptide, including improved inhibition of IL-4 secretion (Table 9), increased stability, prolonged half-life (Tables 2, 5, 7) and improved affinity for CD81 (Figure 2A-B of R3). Applicant further argues that the improved activity cannot be attributed solely to increase stability, but instead results from a combined effect of stability and biological activity.
Applicant’s arguments have been fully considered but not found persuasive. Applicant relies on Tables 2 and 7 to demonstrate that SIP-D00 exhibits greater stability and longer half-life relative to the SP peptide. For example, Table 2 shows the SP peptide recovery decreases to 1.67% at 60 minutes, while DIPI-D00 remains intact. Table 7 shows SIPI-D00 has a half-life of 1.5 hours, compared to 8 minutes of the SP peptide. However, these results are consistent with the teachings of the prior art and therefore expected. Lifetein teaches that substitution of L-amino acids with D-amino acids increases resistance to proteolytic degradation and improves peptide stability. Because peptides composed of L-amino acid are rapidly degraded by proteases, it would have been expected that converting the Cheng peptide into a D-amino acid analog would result in increased metabolic stability and prolonged half life. Accordingly, the improved stability demonstrated by applicant is a predictable result of D-amino acid substitution rather than an unexpected property.
Applicant further argues that SIPI-D00 demonstrates improved inhibition of IL-4 secretion relative to the SP peptide (Table 9). Applicants rely on Tables 9-10 to argue that SIPI-D00 exhibits significantly superior inhibition of IL-4 secretion compared to SP peptide, and therefore the results are unexpected. The Examiner respectfully disagrees. SIPI-D00 is the retro inversion of SP-sequence reversed with D-amino acid at every position. Liftein teaches that retro inversion peptides retain the spatial side-chain orientation of the parent peptide, exhibit increased proteolytic stability, prolonged in vivo persistence and that peptides incorporating D amino acids may, due to increased stability, show greater functional activity. Thus the type of improvement Applicants report is an unexpected and predictable consequence of increase stability rather than an unexpected property.
Furthermore, the statistical annotations in Table 9 indicate significance relative to 0 ug/ml control not significance between SP and SIPI-D000 at the same concentration. No statistical comparison is done between SP and SIPI-D00. Therefore the data do not demonstrate that SIPI-D00 is statistically superior to SP at any dose. Both SP and SIPI-D00 show activity to the related negative control Absent a head to head statistical comparison, applicants have not shown a statistically significant differences between the peptides (see MPEP 716.02(b)). MPEP716.02 (b) states “the evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance."
The Examiner would like to further point out that the experimental method used in Example 3 involves incubating spleen lymphocytes with each peptide for 24 hours prior to measurement of IL-4 (see section 3.2 of specification). Liftein teaches that retro-inversion peptides composed of D-amino acids were significantly more resistant to proteolytic degradation and exhibit prolonged stability (this is also seen in Tables 6-8 in Applicant’s specification). In contrast L peptides would degrade more rapidly in the biological media. Accordingly, during the 24 hour incubation period used in the IL-4 assay, SIPI-D00 (all D retro inverso peptide) would be expected to remain and persist in the environment for a longer period of time and continue exerting its effect while SP peptide would be expected to undergo proteolysis more quickly. Thus, any increase in apparent IL-4 inhibition by SIP-D00 relative to SP is a predictable consequence of the increased proteolytic stability of the D-amino acid peptides as taught by Liftein.
Applicant further cites R3 to demonstrate that SIPI-D00 exhibits improved binding affinity for CD81. However, the increased binding affinity shown is modest and remains within the same order of magnitude as the SP peptide. Additionally, because D-amino acid peptides are significantly more resistant to degradation, the peptide remain intact longer during binding assays which can lead to increased apparent binding affinity. Accordingly, the CD81 binding data does not demonstrate a property that would have been unexpected to one of ordinary skill in the art.
Furthermore, Applicant argues that LifeTein webpage should not be considered prior art because the publication date of the webpage could not be located and the webpage cites a reference published in 2023. Applicant asserts the webpage content may have been disclosed after 2023. Applicant’s arguments have been fully considered but not found persuasive. The Examiner has confirmed that the LifeTein webpage was publicly available prior to the effective filing date of the present application. The Examiner attached the reference with the publication date present of 8/14/2018 (see the NPL reference that was attached July 10, 2025). In the previously attached document (July 10, 2025) there are not references with the date of 2023. The date of publication is clearly indicated on every page at the top and on the last page at the bottom. Accordingly, the reference qualifies as prior art.
The arguments filed in the response on March 26, 2026 are the same arguments provided in the declaration and response to these arguments are provided above under the “Declaration under 37 C.F.R. 1.132” section. In addition, Applicants argue the R1 reference demonstrates that Retroinverso (RI) peptides generally exhibit reduced binding affinity, and therefore one of ordinary skill in the art would not have had a reasonable expectation of success in modifying the peptide of Cheng to arrive at the claimed invention.
Applicant’s arguments have been fully considered but not found persuasive. However, R1 does not uniformly teach a loss of function. Rather R1 discloses that R1 peptides exhibit multiple advantageous properties, including increased intracellular concentration, resistance to proteolysis, and membrane penetrating capability. RI specifically states “Indeed, incubation of neurons in the presence of either the parent Antp-derived peptide or its RI form resulted in 3.4-fold higher intracellular concentration of the latter substrate. Importantly, retro-inversion of peptides presenting potent T-cell epitopes causes a loss of their ability to bind to MHC II molecules and turns them into poor immunogens. Therefore, a combination of resistance to proteolysis, good membrane penetrating capacity, and lack of immunogenicity and antigenicity makes the RI membrane-penetrating peptides into important potential molecular delivery vehicles. Linking the RI protein transduction“(see page 11, right column, second paragraph). These properties support continued biological utility. R1 explicitly teaches enhanced potency (page 8, left hand column). RI teaches that RI peptides resulted in peptides with more potent activity (see First paragraph, page 8, left column). Thus, R1 demonstrates that RI peptides may exhibit a range of activity outcomes, including both reduced binding in some contexts and improved activity in others. Accordingly, R1 does not teach away from the use of RI peptides. Instead, it reinforces that RI modification is a known technique for altering peptide properties including improved stability and in some cases, enhances activity. Moreover, Lifetein teaches that RI peptides retain biological activity while enhancing proteolytic stability. One of ordinary skill in the art would have been motivated to apply RI modification to the peptide of Cheng to improves stability and in vivo performance, with a reasonable expectation that useful biological activity would be maintained. MPEP states “Obviousness does not require absolute predictability, but at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness” (see MPEP 2143.02).
New Rejection
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 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.
Claim(s) 1, 3, 5 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Cheng* (WO2009127140 A1) in view of Liftein (https://www.lifetein.com/Peptide-Synthesis-D-Amino-Acid.html, online 2014, cited previously), and Vught (Science, Vol. 266, 1994, pages 776-778).
Cheng* teaches a method of liver disease comprising administering the peptide GQTYTSG, GQTYTSGG (see claims 1, 5). Regarding claim 5, Cheng* teaches administering the peptide in combination with a pharmaceutically acceptable carrier (see claim 6).
The peptides of Cheng* encompass the reverse sequence of instant SEQ ID NO:2 and an additional amino acid at the c-terminus. Cheng does not teach the sequence of instant SEQ ID NO:2 and d-amino acids thereof.
However, Liftein teaches “Retro-inverso peptides are composed of D-amino acids that are assembled in the reverse order of their parental L-sequences. Retro-inverso peptides are obtained by replacing the normal L-amino acid residues with the corresponding D-amino acids and reversing the direction of the peptide backbone. Therefore, the original spatial orientation and the chirality of the side chains is unchanged. This results in a non-complementary side chain topochemistry between the analog and the parental L-peptide. Advantages of retro-inverso peptides: Retention of protein bioactivity, Long-lasting proteolytic stability in vivo and Antigenic mimicry of natural L-peptides” (See page 2). D-amino acids are more resistant to proteases (see pages 3-4) which in turn prolongs activity.
It would have been obvious before the effective filing date of the claimed invention to create a retro-inverso analog of the peptide of Cheng*. One of ordinary skill the in art would have been motivated to do so to create a more stable peptide with long lasting proteolytic stability in vivo and retained protein bioactivity for a longer period of time. There is a reasonable expectation of success given enhanced proteolytic stability and retained bioactivity are desired properties for therapeutic agents.
Regarding claim 3, the retro-inverso sequence of SEQ ID NO:2 of Cheng* results in a peptide comprising SEQ ID NO:2 with all D-amino acids thus meeting the limitations of instant claim 3.
Regarding claim 18, Cheng* teaches an additional c-terminal amino acid (X8) which would be a D-amino acid with retro inversion. Cheng* does not teach an additional N-terminal amino acid (X0). However, Cheng* does teach that N-terminus can be modified (see paragraph 23) for cyclization, fusion or conjugation (see paragraphs 22, 24 )
Vught teaches that “The oldest and most straightforward method for labeling proteins is via the primary amino groups on lysine residues and at the N-terminus” and conjugation via preferential N-terminal labeling (first page, right column, first paragraph). Vught also teaches that “Proteins with N-terminal cysteines have been successfully used for reactions with thioesters and applied for fusion proteins through native chemical ligation” (See page 2, left hand column, third paragraph).
Cheng teaches peptide variants including GQTYTSGA and GQTYTSGG, demonstrating that the peptide sequence may be modified by addition of amino acid residues at the terminus. This indicates that terminal modification of the peptide sequence was known in the art. A person of ordinary skill in the art would therefore have reasonably considered modifying either terminus of the peptide sequence, including addition of an amino acid residue at the N-terminus for further conjugation or labeling. Vught further teaches that the N-terminus of peptides is a common site for chemical modification and conjugation via lysine or cysteine addition. As peptides of this length contain only a limited number of residues and the number of potential terminal modification is small and predictable, it would have been obvious before the effective filing date of the claimed invention to try adding an amino acid residue (such as Lys or Cys) at the N-terminus for further protein conjugation/chemical modification with a reasonable expectation of success (see MPEP 2143).
Upon application of the retro-inversion approach taught by LifeTein, the added amino acid residue would correspondingly be present as a D-amino acid residue thus meeting the limitations of instant claim 18.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERINNE R DABKOWSKI whose telephone number is (571)272-1829. The examiner can normally be reached Monday-Friday 7:30-5:30 Est.
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/ERINNE R DABKOWSKI/ Examiner, Art Unit 1654
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