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 .
Claim 1, 2, 7 and 11 has been amended.
Claims 1-5, 7, 11-16, 18-20, 22, 24 and 29 are pending.
Claims 6, 8-10, 17, 21, 23 and 25-28 are cancelled.
Claims 12-14, 18-20, 22, and 24 are withdrawn.
Note, rejections and objections not reiterated from previous office actions are hereby withdrawn. The following rejections or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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.
Claims 1-5, 11, 15, 16, 29 are rejected under 35 U.S.C. 103 as being unpatentable over WESTERLUND (Radionuclide Therapy of HER2-Expressing Human Xenografts Using Affibody-Based Peptide Nucleic Acid–Mediated Pretargeting: In Vivo Proof of Principle. The Journal of Nuclear Medicine. 2018.) in view of PE BIOSYSTEMS (Guidelines for Sequence Design of PNA oligomers. 1998.).
Regarding claim 1, WESTERLUND teaches a conjugate comprising a targeting moiety, such as ZHER2:342, that is attached to a hybridization probe moiety comprising a PNA oligomer, such as HP1 (page 1093, paragraph 6). A second conjugate comprising a second hybridization probe moiety comprising a second PNA oligomer, such as HP2 (page 1093, paragraph 6). HP2 is complementary to HP1 (abstract). 177Lu was attached to HP2 (abstract), which reads on a diagnostic agent or a therapeutic agent moiety.
Regarding claims 2-4 and 29, WESTERLUND teaches ZHER2:342 targets the human epidermal growth factor receptor 2 (HER2)–expressing cancer (abstract), which is a mammalian protein which is expressed on the surface of a cell, specifically a tumor cell for breast cancer (page 1093, paragraph 2).
Regarding claim 5, WESTERLUND teaches the conjugate utilizes a HER2-targeting Affibody (abstract), which is an engineered scaffold protein, which acts as a mimetic antibody.
Regarding claim 15, WESTERLUND teaches the conjugate generates a signal that is detectable via single photon emission computed tomography (SPECT) (page 1095, paragraph 2).
Regarding claim 16, WESTERLUND teaches the diagnostic agent used is a radionuclide, such as 177Lu (page 1095, paragraph 2).
WESTERLUND does not teach the length of the second PNA oligomer to be between 5 and 12 bases.
PE BIOSYSTEMS teaches that PNA oligomers have a high affinity without needing to be long and for most applications an oligomer length of 12 to 15 is optimal and in many cases even shorter probes work well (page 1, paragraph 3). The shorter the probe is the more specific it is (page 1, paragraph 3). The longer the probe is the more likely it is to aggregate and harder it is to purify and characterize (page 1, paragraph 3).
Regarding claim 1 and 11, the reference does not specifically teach the length of the second PNA oligomer as claimed by the Applicant. The length of the second PNA oligomer is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of the ordinary skill to determine the optimal length of the second PNA oligomer in order to best achieve desired results, such as having it shorter to have a high affinity, make a more specific probe, easier to purify and characterize, and prevent aggregation. Thus, absent of some demonstration of unexpected results from the claimed parameters, this optimization of the length of the second PNA oligomer would have been obvious at the time of Applicant’s invention.
Claims 1-5, 7, 11, 15, 16, 29 are rejected under 35 U.S.C. 103 as being unpatentable over WESTERLUND (Radionuclide Therapy of HER2-Expressing Human Xenografts Using Affibody-Based Peptide Nucleic Acid–Mediated Pretargeting: In Vivo Proof of Principle. The Journal of Nuclear Medicine. 2018.) and PE BIOSYSTEMS (Guidelines for Sequence Design of PNA oligomers. 1998.) in view of BARHOUMI (US 2020/0095577 A1).
WESTERLUND and PE BIOSYSTEMS teach Applicant’s invention as discussed above.
WESTERLUND and PE BIOSYSTEMS do not teach adding a solubilizing moiety.
Regarding claim 7, BARHOUMI teaches conjugates involving PNA oligomers that are used for detection in a sample (abstract), including use for breast cancer (page 26, paragraph 0412). The conjugates are complimentary to each other (page 4, paragraph 0103). BARHOUMI teaches the conjugate may comprise a group that increases the water solubility (page 11, paragraph 230), such as a PEG based linker (page 14, paragraph 0300), which reads on a solubilizing moiety. The ability of the sequence to dissolve in aqueous solutions assists in conjugation to antibodies (Page 11, paragraph 0233). BARHOUMI further teaches that PNA hydrophobicity is proportional to the number of bases a PNA sequence has. The more bases a PNA sequence has the higher the hydrophobicity is (Page 11, paragraph 0233). The hydrophobicity can affect how the sequence dissolves in aqueous solutions for conjugation to antibodies, how the PNA loads and the stability of the conjugate (Page 11, paragraph 0233).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate a solubilizing moiety. The person of ordinary skill in the art would have been motivated to make those modifications, because it affects the water solubility of the conjugate which affects the ability of the sequence to dissolve in aqueous solutions assists in conjugation to antibodies and reasonably would have expected success because the references are in the same field of endeavor, such as complimentary conjugates comprising PNA oligomers that are used for diagnostic purposes in breast cancer. Furthermore, both references talk about conjugating a form of antibody, WESTERLUND uses an antibody mimetic.
Response to Arguments
Applicant argues, Westerlund discloses a complementary affibody-conjugated PNA duplex containing a 15-mer primary PNA oligomer together with a complementary 15-mer secondary PNA oligomer, and further discloses that the primary oligomer may be pre-administered in order to obtain an improved tumor-to-kidney ratio. See Westerlund, page 1092. In contrast, the invention according to instant amended claim I differs from Westerlund in that the secondary PNA oligomer is 8-12 bases short. According to the Examiner's own assertion, "Westerlund does not teach the length of the second PNA oligomer to be between 5 and 12 bases or adding a solubilizing moiety" and "[Barhoumi] does not specifically teach the amount of bases in the probes as claimed by the Applicant". Office Action, pages 5-6. Thus, the cited references neither teach nor suggest all the elements of instant amended claim 1.
The examiner does not find the argument persuasive because, as discussed above, PE BIOSYSTEMS teaches a 12-mer PNA oligomer and it would be obvious to adjust the length of the oligomer to best achieve desired results, such as having it shorter to have a high affinity, make a more specific probe, easier to purify and characterize, and prevent aggregation.
Applicant argues, the cited references do not provide any motivation for a person of ordinary skill in the art to use a shorter secondary PNA oligomer to solve the objective problem in the art, namely the provision of an improved PNA-mediated pretargeting system having a more favorable biodistribution profile, in particular reduced kidney uptake and an improved tumor-to-kidney ratio, while maintaining efficient tumor targeting. See Westerlund, pages 1092-93; see also Application, pages 1-3. Barhoumi does not teach or suggest that shortening of the second oligomer would specifically lead to a better tumor-to-kidney ratio. See generally, Barhoumi. Meanwhile, Westerlund acknowledges the kidney-related biodistribution problem and addresses it by preadministering the primary oligomer. See id Thus, not only do the cited references not suggest that a shorter secondary PNA oligomer would lead to improved biodistribution, but Westerlund in fact teaches away from the instantly claimed solution of providing a shorter secondary PNA oligomer.
The examiner does not find the argument persuasive because as discussed above, PE BIOSYSTEMS teaches a 12-mer PNA oligomer and it would be obvious to adjust the length of the oligomer to best achieve desired results, such as having it shorter to have a high affinity, make a more specific probe, easier to purify and characterize, and prevent aggregation. The fact that WESTERLUND acknowledges the kidney-related biodistribution problem and addresses it by preadministering the primary oligomer, is not a teaching away. As many techniques can be utilized together to improve biodistribution, not just one.
Applicant argues, the use of shorter secondary PNA probes decreases kidney accumulation significantly relative to a 15-mer probe (i.e., HP2) as was used in Westerlund. For example, the 9-mer probe HP16 exhibited renal uptake of 6±1 % ID/g at 4 h post injection, compared with 10±2% ID/g for the 15-mer HP2 probe. See Application, page 33. At the same time, tumor uptake remained high (24±6% ID/g for HP 16 versus 19± 1 % ID/g for HP2). Id Consequently, the shortened probes provided substantially improved tumor-to-kidney ratios. In particular, the ratio of areas under the time-activity plots for tumor versus kidney was 3.8 for the 9-mer (HP16) and 2.8 for the 12-mer (HPl 7), as compared with 2.0 for the 15-mer (HP2 and HP18 probes). See Application, Table 6. Thus, despite the reduced oligomer length, Applicant has shown that the shorter probes retained sufficiently strong hybridization affinity and high tumor targeting performance. This difference provides the unexpected effect of improved in vivo biodistribution as compared to the use of a 15-mer secondary probe. See Application, page 32, lines 9-11 and 24-26; Figure 5; Table 5.
In order to overcome a prima facie case of obviousness, it is incumbent upon the Applicant to provide comparative test evidence that demonstrates unexpected superiority of the claimed compositions versus the closest prior art compositions, and not simply an advantage predictable from the prior art. See In re Chapman, 148 USPQ 711, 715 (CCPA, 1966). Moreover, such proffered comparisons must be commensurate in scope with the breadth of the claims. See In re Clemens, 206 USPQ 289, 296 (CCPA, 1980) and In re Coleman, 205 USPQ 1172, 1175 (CCPA 1980). In the instant case, PE BIOSYSTEMS teaches the use of a 12 base PNA oligomer and goes further to say shorter can be used. Additionally, PE BIOSYSTEMS teaches that PNA oligomers have a high affinity without needing to be long and for most applications an oligomer length of 12 to 15 is optimal and in many cases even shorter probes work well. The shorter the probe is the more specific it is. The longer the probe is the more likely it is to aggregate and harder it is to purify and characterize.
PE BIOSYSTEMS teaches the high affinity Applicant claims is “unexpected”.
For a complete discussion of unexpected results, Applicants are referred to MPEP 716.02 et seq.
Conclusion
Applicant's amendment necessitated the new 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 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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/S.L.M./ Examiner, Art Unit 1618
/Michael G. Hartley/ Supervisory Patent Examiner, Art Unit 1618
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