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 .
Receipt is acknowledged of Applicant’s Request for Continued Examination and Amendment filed on 12/24/2024; and IDS filed on 12/24/2024.
Claims 17, 32-34 have been amended.
Claim 43 has been added.
Claim 31 has been canceled.
Claims 17-20, 22-30, 32-43 are pending in the instant application.
Claims 18-20, 22, 29, 33-34 have been previously withdrawn from consideration.
Note, rejections and objections not reiterated from previous office actions are hereby withdrawn.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.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/24/2024 has been entered.
Claim Rejections - 35 USC § 112, 4th paragraph
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 37 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 37 does not further limit independent claim 17, because claim 17 recites these limitations. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 17, 23-28, 30, 32, 35-37, 42-43 is/are rejected under 35 U.S.C. 103 as being unpatentable over MIRKIN et al (US 2012/0283316; hereinafter “MIRKIN1”) as incorporated with MIRKIN et al (US 2009/0209629; hereinafter “MIRKIN2”) in view of WANG et al (Matrix metalloproteinase 2-responsive micelle for siRNA delivery. Biomaterials 35 (2014) 7622-7634).
MIRKIN1 teaches an oligonucleotide-nanoparticle (see abstract) composition for administer to a patient that can traverse a cell membrane (see [0026]) comprised of: a nanoparticle, such as gold (see [0015]), wherein oligonucleotide functionalized thereto (see abstract; [0008]), because the oligonucleotide increases the nanoparticles to transverse cellular membranes/cellular uptake (see [0018]) such as HeLa tumor cells (see [0020]; [0063]). An example of the composition is PEG-Cy5-DNA-AuNP in Example 1(see [0121]), which reads on PEG-oligonucleotide-nanoparticle (Note, the Cy5 is a dye used for detection). Additional disclosures include: oligonucleotide may possess gene regulatory activity (see [0026]); density of oligonucleotides on the surface of the NP can be tuned for a given application, such as, the density of DNA on the NP surface affected the rate at which it was degraded by nucleases (see [0087]) and stability (see [0089]), such as about 40pmol/cm2 (see [0089]); methods of attaching RNA are described in US 2009/0209629 (MIRKIN2) and is incorporated by reference (see [0082]); therapeutic agent (see abstract); PEGylation to increase bioactivity and decrease adverse reaction (see [0117]); MIRKIN1 also teaches peptide cleavable linkers by enzymes, such as matrix metalloprotease enzyme, can be used (see [0085]), but does not specifically teach using it as a linker for the PEG molecule.
MIRKEN2, which is incorporated in MIRKIN1, teaches methods for regulating gene expression (see abstract), such as inhibiting expression of a gene (see [0005]), which reads on inhibition of gene expression, using nanoparticles functionalized with oligonucleotides (see abstract), wherein oligonucleotides contemplated for attachment to a nanoparticle include those which modulate expression of a gene product (see [0057]), such as siRNA oligonucleotides (see [0057]; [0062]). Thus, it would have been obvious to use siRNA for modulating gene expression, such as inhibition of gene expression, and adjusting the amount for the desired amount of inhibition.
MIRKIN1 teaches using PEG, but does NOT teach using PEG with an enzyme-sensitive peptide linker, such as PLGLAG (SEQ ID NO:1); or expression of human epidermal growth factor receptor 2 (Her2) is modulated.
WANG teaches using PEG with and enzyme-sensitive peptide linker, such as PLGLAG (see abstract), because the prior art had known of PEGylation of nanoparticles is highly desirable for systemic siRNA delivery in terms of the attribute of prolonged circulation (see pg. 7622, 2nd col); however, PEGylation significantly reduces the cellular uptake of nanoparticles (see pg. 7622, 2nd col). Recently, protease responsive nanoparticles, which can overcome the above conflicting design by deshielding/shedding the PEG shell following accumulation by tumor cells in vivo, have attracted much attention (see pg. 7623, 1st col). Matrix metalloproteinase 2 (MMP-2) is a protease that engages in the degradation of extracellular matrices in tumor, and it is relatively overexpressed in almost all tumors compared with normal tissues. It has been proven that MMP-2 responsiveness can be eminently sensitive and highly specific in tumors, which is promising in cancer therapy and cancer imaging (see pg. 7623, 1st col). Additional discloses include: the peptide PLG*LAG, has specific cleavage site for the MMP-2 in order to decladding/shedding the PEG layer (see abstract; and pg. 7623, 2nd col), which would result in PEG-peptide liner conjugation (see abstract); cationic peptide polyarginie r9 provides siRNA binding function and cellular membrane penetration/uptake (see pg. 7623; 2nd col), which is similar to the same function as the oligonucleotide in MIRKIN1; carrying siRNA against Polo-like kinase 1 (PLK1; see abstract), which suppresses Her2+ breast cancer growth (see reference #10 at pg. 7633), and reads on expression of human epidermal growth factor receptor 2 (Her2) is modulated.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate a PEG with enzyme-sensitive peptide linker, such as PLGLAG (SEQ ID NO:1). The person of ordinary skill in the art would have been motivated to make those modifications, because it would be an improvement by providing prolonged circulation, as disclosed in MIRKEN1, until accumulated at the tumor site, wherein the linker would be cleaved to release/shed the PEG shell in order for the nanoparticle to be uptake into the tumor cells, and reasonably would have expected success because the prior art had known of using PEGylation.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate siRNA expression of human epidermal growth factor receptor 2 (Her2) is modulated. The person of ordinary skill in the art would have been motivated to make those modifications, because it would treat breast cancer, and reasonably would have expected success because the all the references dealt in the same field on endeavor and WANG showed that this type of siRNA works with PEG with an enzyme-sensitive peptide linker, such as PLGLAG (SEQ ID NO:1), to suppress HER2 in breast cancer, which reads on modulate gene expression.
The references do not specifically teach adding the ingredients in the density amount of PEG as claimed by Applicant. The amount of a specific ingredient in a composition 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 ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve the desired results, such as increased bioactive and decrease adverse reaction. Thus, absent some demonstration of unexpected results from the claimed parameters, this optimization of ingredient amount would have been obvious at the time of Applicant's invention.
Claims 17, 23-28, 30, 32, 35-43 is/are rejected under 35 U.S.C. 103 as being unpatentable over MIRKIN et al (US 2012/0283316; hereinafter “MIRKIN1”) as incorporated with MIRKIN et al (US 2009/0209629; hereinafter MIRKIN2) in view of WANG et al (Matrix metalloproteinase 2-responsive micelle for siRNA delivery. Biomaterials 35 (2014) 7622-7634) and FAHMY et al (US 2015/0064265).
As discussed above, MIRKIN1, MIRKIN2 and WANG teach Applicant’s invention.
MIRKIN1 does not teach the size of the PEG for PEGylation, such as PEG2000.
FAHMY teaches the prior art had used PEG2000 for PEGylation to incorporate polyethylene glycol onto the surface to increase stability and circulation time (see [0099]), which would increase bioactivity.
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to incorporate PEG2000 for PEGylation. The person of ordinary skill in the art would have been motivated to make those modifications, because PEG2000 was used for PEGylation and reasonably would have expected success because MIRKIN1 teaches using PEGylation to increase bioactivity.
Response to Arguments
Applicant argues that as acknowledged by the Office, Mirkin 1 does not disclose using an enzyme as a linker for a PEG molecule. The Office asserted that the claimed method would have been obvious from combining Mirkin 1 and Mirkin 2 in view of Wang (or Mirkin 1 and Mirkin 2 in view of Wang and Fahmy). The Applicant disputes these analyses. The Office has not established that the claimed method was predictable to one of ordinary skill in the art or that there was a reasonable expectation of success at arriving at the method of claim 17. Amended claim 17 recites that the oligonucleotide to which the PEG is attached is an inhibitory oligonucleotide that modulates gene expression. Assuming strictly for the sake of argument that one of ordinary skill in the art did arrive at the SNA recited in claim 17, which Applicant disagrees with, the Office has not established that it would have been predictable or that there would have been a reasonable expectation of success that such a SNA could modulate gene expression. It was unpredictable whether the action of cleaving the PEG from the SNA of the instant claims would affect the function of the oligonucleotide to which the PEG was attached. The Office has therefore not established that there would have been predictability or a reasonable expectation of success for any pending claim.
The Examiner finds this argument unpersuasive, because as discussed in the rejection, WANG has shown that siRNA works with PEG with an enzyme-sensitive peptide linker, such as PLGLAG (SEQ ID NO:1), to suppress HER2 in breast cancer, which reads on modulate gene expression. Thus, there is reasonable expectation of success.
Telephonic Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAKE MINH VU whose telephone number is (571)272-8148. The examiner can normally be reached Mon-Fri 9:00am-5:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Hartley can be reached at (571) 272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JAKE M VU/Primary Examiner, Art Unit 1618