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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 filed on 03/20/2026 has been entered.
Claims 1-16 as currently amended/presented are pending in this application.
Claims 13-16 (non-elected invention of Group II) remain withdrawn.
Claims 1-12 (elected invention of Group I, with traverse; directed to “A theranostic composition…”), as currently amended/presented, have been examined on their merits in this action.
Priority
This application is a 371 of PCT/IB2020/054086 (filed on 04/30/2020), which claims benefit from a US provisional application 62/841,828 filed on 05/01/2019.
Claim-Specification Objections -Withdrawn
In view of applicant’s amendment to claim 1 and specification of record (SPEC, paragraph [0024]) for the full chemical name limitation of “PNU-159682”, the objections as previously made by the examiner, have been withdrawn.
The following contains new grounds of objection/rejection over the pending claims as currently amended by applicants.
Claim Rejections - 35 USC § 112 - New
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 10 (as presented) is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 10 recites the following:
“10. (Previously Presented) The theranostic composition of claim 1, wherein the first minicell surface component and/or the second minicell surface component comprises a lipopolysaccharide (LPS), and optionally wherein an O-polysaccharide of the lipopolysaccharide is radiolabeled.”
It is noted that claim 1 (from which claim 10 directly depends from) has now been amended (in last two lines) to recite the limitations “wherein the first component of the minicells and the second component of the minicells are different surface components”, which is contradictory to the limitations presented in instant claim 10. Claim 10 as presented encompasses the product as claimed, wherein the first component of the minicells and the second component of the minicells are the same surface component, i.e. lipopolysaccharide. Therefore, it is unclear as to how “the first component of the minicells and the second component of the minicells are different surface components”. The metes and bounds of the claimed invention as currently presented does not appear to be properly defined. Appropriate correction is required.
NOTE: 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.
Claim Rejections - 35 USC § 103 - New Grounds
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.
1. Claims 1-12 (as currently amended/presented) are/remain rejected under 35 U.S.C. 103 as being unpatentable over Brahmbhatt et al (US 9,987,377 B2; USPAT cited in IDS dated 10/27/2021; referred herein as Brahmbhatt et al ‘377) taken with Brahmbhatt et al (US 9,844,598 B2; USPAT previously of record; referred herein as Brahmbhatt et al ‘598), Quintieri et al (2005; NPL previously of record), Brahmbhatt et al (WO 2005/079854 A1; FOR previously of record; referred herein as Brahmbhatt et al WO’854), and Moreno et al (2016; NPL previously of record).
Claim 1 (as currently amended) is directed to “A theranostic composition comprising:
(a) a plurality of purified, intact bacterially derived minicells;
(b) at least one anti-neoplastic agent comprised within the minicells, wherein the at least one anti-neoplastic agent comprises 3'-deamino-3",4'-anhydro-(2"(S)-methoxy-3"(R)-oxy-4"-morpholinyl)doxorubicin (PNU-159682);
(c) a bispecific ligand, wherein the bispecific ligand is attached to a first surface component of the minicells, and wherein the bispecific ligand comprises:
(i) a first arm with binding specificity for the first surface component; and
(ii) a second arm with binding specificity for a tumor cell surface receptor; and
(d) a monospecific ligand attached to a second surface component of the minicells, wherein the monospecific ligand has at least one radio-imaging agent conjugated to the monospecific ligand at one or more conjugation residues of the monospecific ligand, wherein the radio-imaging agent is a therapeutic radiation emitting agent and comprises a radioisotope, magnetic nanoparticle, organic fluorescent dye, or any combination thereof,
wherein the first component of the minicells and the second component of the minicells are different surface components.”
See also limitations of dependent claims 2-12, as currently presented.
It is to be noted that as presented, instant claim 1 does not specifically define any specific “first” and/or “second” cell “surface component”, per se, neither does the instant disclosure of record (see for example, Summary of the invention starting on p. 3)
Figure 1 provided by applicants discloses the following details:
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It is also to be noted that the term “therapeutic radiation” has not been specifically defined by the applicants on record. The instant disclosure provides the following generic guidance on page 4, [0016] that relates to a “tumor size” reduction as an example (see also [0043]):
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Brahmbhatt et al ‘377, while teaching compositions and methods for targeted gene delivery to non-phagocytic mammalian cells via bacterially-derived intact minicells (see title, Abstract, Summary of the invention, and Claims 1-14), disclose a theranostic composition comprising: (i) purified, intact bacterially derived minicells comprising a therapeutic nucleic acid molecule; (ii) a bispecific antibody or antibody fragment having specificity for a cancer cell surface receptor and the minicell, wherein the bispecific antibody or antibody fragment is bound to the minicell; and (iii) a pharmaceutical acceptable carrier, wherein the bispecific antibody or antibody fragment comprises a first multivalent arm that carries specificity for a bacterially derived minicell surface structure and a second multivalent arm that provides binding specificity for a cancer cell surface receptor (such as epidermal growth factor receptor, EGFR that is known to be highly expressed in a range of solid tumors including those of the breast, head and neck, non-small cell lung and prostate; see column 8, last 2 paragraphs, for instance), wherein the cancer cell surface receptor is capable of activating receptor-mediated endocytosis of the minicell; wherein a desirable minicell surface structure for ligand binding is an O-polysaccharide component of a lipopolysaccharide (LPS; see column 3, “Summary of the Invention”, 2nd paragraph, for instance; can be taken as the “first minicell surface component” of instant claim 1, as amended); wherein Brahmbhatt et al ‘377 also disclose the fact that “Other minicell surface structures that can be exploited for ligand binding include cell surface exposed polypeptides and carbohydrates on outer membranes, pilli, fimbrae and flagella” (see col. 8, lines 41-44, for instance); and wherein the composition is free of contamination removable through 100 nm filtration and wherein the minicells are approximately 400 nm in diameter (see claims 1-14, for instance). They disclose that the therapeutic nucleic acid molecule can comprise functional DNA segment coding for an enzyme to generate cytotoxic metabolites, agents to induce apoptosis or cell death, gene therapy and anti-cancer agents including antisense RNA or small interfering RNA (siRNA), or other anti-neoplastic agents that are useful in treating cancer and variety of other disorders (see detailed disclosure on columns 11-12, for instance). They also disclose a “reporter element” that confers on its recombinant host a readily detectable phenotype or characteristic, typically by encoding a polypeptide, not otherwise produced by the host, that can be detected, upon expression, by histological or in situ analysis, such as by in vivo imaging techniques (see Brahmbhatt et al’377, column 13, lines 58-64, for instance). Thus, Brahmbhatt et al ‘377 disclose multiple desirable minicell surface components (including cell surface carbohydrates, polypeptides, pilli, flagella, etc.) that can be liganded to prepare such anti-neoplastic minicell compositions.
However, a composition, wherein (1) a monospecific ligand (attached to a minicell surface) has at least one radio-imaging agent (that also emits “a therapeutic radiation”) conjugated to the monospecific ligand at one or more conjugation residues of the monospecific ligand (instant claim 1, and limitations of instant claims 4-6 and 10); wherein (2) the anti-neoplastic agent comprises PNU-159682 (a “super-cytotoxic drug”; see instant claim 1 as amended, and applicant’s disclosure in [0024], wherein PNU-159682 is disclosed as an exemplary super-cytotoxic anti-neoplastic agent); and 3) wherein “the first component of the minicells and the second component of the minicells are different surface components” (see amended claim 1), have not been explicitly disclosed by Brahmbhatt et al’377, as discussed above.
Brahmbhatt et al ’598, while teaching bacterially derived intact minicells for delivery of therapeutic agents to brain tumors (see title, Abstract, Summary, section “Radionuclides” on columns 11-12, and claims), disclose the composition that comprises a radionuclide as anti-neoplastic agent, wherein the radionuclide is attached to a protein or a carbohydrate on the surface of said intact minicells, or wherein the radionuclide is attached to the bispecific antibody that is associated with the surface of the minicells; wherein the radionuclide (i.e. radioisotope) is selected from yttrium-90, technetium-99m, iodine-123, iodine-131, rubidium-82, thallium-201, gallium-67, fluorine-18, xenon-133 , and indium-111; wherein the radio-labeled minicells can also be imaged using Single-Photon Emission Computed Tomography (SPECT) having a gamma camera fitted with low energy, all purpose parallel hole collimators (see Example 9, disclosure on columns 33-34; and Figure 11, for instance); and wherein the said composition contains about 30 Gy to about 100 Gy radioactivity (see claims 2-6, for instance). Brahmbhatt et al ’598 disclose the fact that oligosaccharides on the minicell surface also can be radiolabeled using, for example, well-established protocols (see column 12, 4th paragraph and citation therein, for instance) that comprise O-polysaccharide component of the lipopolysaccharide (LPS) that is endemic to the minicell surface derived from gram-negative bacteria. Brahmbhatt et al ’598 also disclose that said composition may comprise anti-neoplastic agent that comprise “super-cytotoxic drug” which are highly toxic known chemotherapy drugs (see entire section “Chemotherapy drugs” on column 13-14, for instance) that can have a LD50 that is lower than the ED50 of the super-cytotoxic drug for a targeted cancer (see Brahmbhatt et al ’598, column 14, 2nd paragraph, and claim 9, for instance); wherein the anti-neoplastic agent may comprise a functional nucleic acid (see entire section “Functional Nucleic Acids” on columns 15-17, for instance) including small interfering RNAs (siRNAs) or miRNAs which are readily available and well known in the art for regulating a variety of target genes (see claims 11-14, for instance); and wherein the bispecific ligand having specificity to a cell surface receptor (a tumor cell antigen) is an antibody which specifically recognizes said tumor cell antigen (see claim 15-17, for instance).
Although, Brahmbhatt et al ’598 does not exemplify that the super-cytotoxic anti-neoplastic drug is PNU-159682, such was already known in the prior art as explicitly disclosed and demonstrated by Quintieri et al, 2005. Quintieri et al disclose the fact that an oxidative bioactivation product of Nemorubicin (MMDX) by human liver microsomes, known as 3’-deamino-3”,4’-anhydro-[2”(S)-methoxy-3”(R)-oxy-4”-morpholinyl]doxorubicin (PNU-159682) is found to be the most potent oxidative metabolite (see Abstract, Introduction, and page 1609, left column, 2nd paragraph, in particular; and cited references therein), being more than 3,000-fold more cytotoxic than its parent compound, and therefore would be more useful as an anti-neoplastic agent for inhibiting tumor cell growth in vitro, and for in vivo therapeutic efficacy (see page 1609, left column, 2nd paragraph; page 1611, sections “In vitro Cytotoxicity”, and “In vivo Tumor Models and Treatments”, for instance). In addition, Quintieri et al explicitly disclose the comparative IC70 values in nmol/L for doxorubicin, MMDX, and PNU-159682 for human tumor cell lines such as HT-29, A2780, DU145, EM-2, Jurkat and CEM cells (see page 1614, Table 1, for instance), and demonstrate the fact that PNU-159682 was significantly more potent and cytotoxic even at lower sub-nanomolar dose levels for all the tumor cell lines tested. Quintieri et al also state that “…further recent data suggest that PNU-159682 retains its activity against tumor cell lines with different mechanisms of resistance to classical anticancer agents, including MDR-1 gene overexpression, reduced topoisomerase II activity, and mutations in the topoisomerase I gene, these latter genetic alterations conferring resistance in vitro to the parent drug, MMDX (35)” (see page 1615, right column, 1st paragraph), and therefore clearly suggest (to an artisan of ordinary skill in the art) the utility of such anti-neoplastic agent such as PNU-159682 (as super-cytotoxic agent) that can be more effectively employed against tumor cells for therapeutic purposes.
Thus, given the disclosure provided by Brahmbhatt et al ’598 for use of radionuclide as anti-neoplastic agents (i.e. “a therapeutic radiation” emitting agents) that can also be used as radio-imaging agents (having appropriate radiation ranges such as between about 30 Gy to about 100 Gy) that can be conjugated to variety of ligands including at the surface of minicells via O-polysaccharide components of LPS (see applicant’s disclosure on page 10, [0041], wherein the “bispecific ligand and monospecific ligand can each be a polypeptide, a carbohydrate or a combination of a polypeptide and a carbohydrate”; the term “monospecific ligand” per se has not been specifically defined by the applicants on record), and use of variety of super-cytotoxic chemotherapy drugs, including one of the more effective anti-neoplastic agent such as PNU-159682 as taught by Quintieri et al (see detailed discussion above), it would have been obvious to an artisan of ordinary skill in the art to successfully modify the theranostic composition disclosed by Brahmbhatt et al ’377 such that it comprises suitable anti-neoplastic agents such as effective amounts of suitable radionuclides, or super-toxic chemotherapy drugs such as PNU-159682 (at suitable sub-nanomolar concentrations for a desired cell line, or depending on the specific tumor cell type, as explicitly taught by Quintiery et al, see discussion above), or a combination thereof as disclosed and/or suggested by Brahmbhatt et al ’598 when taken with Quintiery et al, in order to be used as effective therapeutic as well as imaging of targeted tumors using the bacterially-derived intact minicells (i.e. as “theranostic” composition as claimed). Since, the use of suitable linker(s) molecules and conjugation methods for variety of ligands were already known and/or disclosed by Brahmbhatt et al ’377, such modifications for useful anti-neoplastic agents, as well as a suitable radionuclide conjugated to the minicell surface that can also work as a radio-imaging agent (i.e. therapeutic as well as diagnostic uses) would have been obvious and/or fully contemplated by an artisan of ordinary skill in the art.
In addition, since Brahmbhatt et al ‘377 already disclose the fact that multiple desirable minicell surface components (including cell surface carbohydrates, polypeptides, pilli, flagella, etc.) can be successfully liganded to prepare anti-neoplastic minicell compositions (see teachings above; col. 8, lines 41-44, for instance), and the fact that Brahmbhatt et al ‘598 also disclose such antineoplastic composition (that comprises a radionuclide as anti-neoplastic agent), wherein the radionuclide can be attached to a protein or a carbohydrate on the surface of intact minicells (see Brahmbhatt et al ‘598, Summary, 2nd paragraph on column 2), an artisan of ordinary skill in the art would have successfully modified the anti-neoplastic minicell composition disclosed by Brahmbhatt et al ‘377 such that it employs different minicell surface components for attaching bispecific antibody and the radionuclide, as per need. Since, both cited references clearly designate and suggest various cell surface components including polypeptides or carbohydrates on bacterial cell membranes, such modification for employing different minicell surface components would have been obvious and/or fully contemplated by an artisan in the drug-delivery art, unless evidence/data and/or criticality presented on record for the entire scope of the claimed product, as currently amended.
However, the composition comprising minicells that comprises a “pharmaceutically effective polymer film or coat”, which reduces opsonization or minimizes uptake by macrophages that includes polymeric film such as polyethylene glycol, PEG (see instant claim 7) has not been explicitly disclosed and/or exemplified by the disclosure from Brahmbhatt et al ‘377 taken with Brahmbhatt et al ‘598 and Quintieri et al, as discussed above.
Brahmbhatt et al WO’854, while teaching composition and methods for targeted in vitro and in vivo drug delivery to mammalian cells via bacterially derived intact minicells (see Title, Abstract, and page 3 2nd paragraph), disclose the art-known fact that synthetic polymeric film or coating (such as of polyethylene glycol, PEG) on vesicles such as liposomes have been known to serve as a barrier, to inhibit or reduce hydrophobic and electrostatic interactions with variety of blood components and plasma opsonins and thereby retarding recognition of liposomes by reticuloendothelial system (that includes circulating macrophages) and thus prolonging circulation time of coated vesicles (see page 3, 2nd paragraph and cited references therein).
Thus, given the teachings from Brahmbhatt et al WO’854, an artisan of ordinary skill in the art of bacterial minicell-based drug delivery would have fully contemplated and successfully employed the use of such synthetic polymeric film and/or coating on the minicell surface in order to prolong their circulation time for better effectiveness in drug delivery method depending on the specific target, or as per need, since such polymeric coatings were known in the prior art to effectively reduce recognition of coated vesicles and opsonization by mammalian blood cells in circulation.
Although, the cited prior art references above do not explicitly exemplify the use of bispecific ligands that comprise cell surface receptors such as Arg-Gly-Asp (RGD) peptide, bombesin (BBN)/gastrin-releasing peptide (GRP), somatostatin, etc. (see instant claim 9), such would have been obvious given the detailed disclosure for such cell surface receptors and their use in tumor targeting for imaging as well as drug delivery or delivery of cytotoxic agents to tumors as disclosed by Moreno et al (see Abstract, entire sections 3, 5-7, for instance), wherein they can comprise radiolabeled analogs coupled to cytotoxic drugs of choice for variety of downstream clinical applications. Thus, such modifications in the compositions disclosed by Brahmbhatt et al ‘377 in view of combined teachings in the cited prior art of record as discussed above, would have been obvious to an artisan of ordinary skill in the art of bacterial minicell-based drug delivery and imaging, unless evidence and/or data provided on record to the contrary (which is currently lacking on record; see instant disclosure, specification page 18, entire section of “D. Imaging Moiety”; and Examples starting on page 54, for instances). The invention as generically claimed (see instant claim 1, as currently amended) fails to distinguish itself over the combined teachings and/or suggestions from the cited prior art references of record, as discussed above.
Thus, the claim as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the invention as currently presented.
As per MPEP 2111.01, during examination, the claims must be interpreted as broadly as their terms reasonably allow. In re American Academy of Science Tech Center, F.3d, 2004 WL 1067528 (Fed. Cir. May 13, 2004)(The USPTO uses a different standard for construing claims than that used by district courts; during examination the USPTO must give claims their broadest reasonable interpretation.). This means that the words of the claim must be given their plain meaning unless applicant has provided a clear definition in the specification. In re Zletz, 893 F.2d 319, 321, 13 USPQ2d 1320, 1322 (Fed. Cir. 1989).
Examiner’s Response to Arguments
Applicant’s arguments filed on 03/09/2026 with respect to claims 1-12 of record as currently amended by applicants (see REM, p. 12-15, regarding the 103(a) rejection of record, mainly pertain to the amended claims) have been noted and fully considered but are moot in view of new grounds of objection/rejection made in this office action, as discussed in details above.
Conclusion
NO claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SATYENDRA K. SINGH whose telephone number is (571)272-8790. The examiner can normally be reached M-F 8:00- 5:00.
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SATYENDRA K. SINGH
Primary Examiner
Art Unit 1657
/SATYENDRA K SINGH/Primary Examiner, Art Unit 1657
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