DETAILED ACTION
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 .
Status of Claims
Claims 1-9, 24-31 and 63-64 are pending.
Claims 3, 5-9, 24-26, 31 and 63 are amended.
Claims 1-9, 24-31 and 63-64 are currently under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The U.S. effective filing date of all claims under examination is set at 03/31/2021 based on the provisional application 63/168,857 (filed 03/31/2021).
Drawings
The drawings are objected to because of the following:
Fig 1: all three sections/parts of Fig 1 are lacking a label for x-axis; and
Fig 2 top: a legend that explains what the three lines represent is lacking,
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 3, 4, 5, 24, 25 and 64 are objected to because of the following informalities:
Claim 3 appears to have several typographical errors. Firstly, the term “Bma/1” in line 3 should be amended to “Bmal1”. Secondly, the word “Clocks” in line 4 should be amended to “clock” so that the claim recites “clock gene promoter”. “Thirdly, the term “ROR/3” in line 7 should be amended to “RORβ”. Fourthly, the terms “CK fa” and “CK18” in line 8 should be amended to “CK1δ” and “CK1ɛ” respectively. In addition, the term “Nfi/3” in line 8 should be amended to “Nfil3”. Finally, the word “and” in line 9 should be amended to “or” such that the claim recites “….or any combination thereof”.
Claim 4 appears to have a typographical error. The word “and” in line 3 should be amended to “or” such that the claim recites “….or any combination thereof”.
Claim 5 appears to be missing the word “the” in line 2 before “transcriptional regulatory…”. The claim should be amended to recite “the transcriptional regulatory….”.
Claim 24 appears to have a typographical error. The word “polypeptides” in line 5 should be amended to “polypeptide” such that the claim reads “….or an anti-cancer polypeptide”.
Claim 25 appears to have three typographical errors. Firstly, a comma should be inserted in line 2 between the terms “IL-10” and “IL-4”. Secondly, the term “Decorin” with a capital letter “D” should be amended to “decorin” since the term/word appears in the middle of the sentence. Thirdly, the word “and” in line 7 should be amended to “or” such that the claim reads “….or any combination thereof”.
Claim 64 appears to have two typographical errors. Firstly, the term “Muscolo dystrophies” in line 5 of Pg 5 should be amended to “muscular dystrophies”. Secondly, the word “and” in line 7 of Pg 5 should be amended to “or” such that the claim reads “….or urinary incontinence”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claims 5-9, 25 and 30 are 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.
Claims 5 recites the phrase “transcriptional regulatory region”. There is insufficient antecedent basis for “transcriptional regulatory region” in the claim. It is suggested that the claim be amended to recite “transcriptional regulatory nucleic acid sequence” as recited in claim 1.
Claims 6-9 recites the phrase “the transcriptional regulatory region”. There is insufficient antecedent basis for “the transcriptional regulatory region” in the claims. It is suggested that the claims be amended to recite “the transcriptional regulatory nucleic acid sequence” as recited in claim 1.
Claim 25 recites the phrase “the therapeutic biologic nucleic acid molecule”. There is insufficient antecedent basis for “the therapeutic biologic nucleic acid molecule” in the claim. It is suggested that the claim be amended to recite “the therapeutic biologic nucleic acid sequence” as recited in claim 24.
Claim 25 recites three phrases in parenthesis, namely “(e.g., prodynorphin)”, “(e.g. proenkephalin)” and “(proopiomelanocortin)”. The metes-and-bounds of the claims are unclear because it is unclear how, or if, possible limitations following “e.g.” or proopiomelanocortin in parenthesis limit the claim.
Claim 30 recites the phrase “wherein the promoter is a Per2 promoter”. There is insufficient antecedent basis for “the promoter” in the claim. It is suggested that the claim be amended to recite “wherein the nucleic acid construct or vector comprises a Per2 promoter”.
Claim Rejections - 35 USC § 103 (first)
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.
Claims 1-6 and 24- 29 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (US20030180947A1 Date Published 2003-09-25) in view of Jacobsen et al. (J Exp Med. 1993 Aug 1;178(2):413-8), Del Vecchio et al. (Clin Cancer Res (2007) 13 (16): 4677–4685) and Kuo and Ladurner (Front Genet. 2020 Jun 19;11:601).
Wu et al. teaches the circadian control of stem/progenitor cell self-renewal and differentiation and of clock controlled gene expression (Title). They teach that a method to modulate the circadian clock system of target cells can be by transfecting a target cell with either a constitutive or an inducible engineered gene that encodes one or more clock elements (paragraph [0034]).
Wu et al. teaches that the ability to control and manipulate the circadian clock system of cells can allow regulated expression of various proteins (i.e. the product of clock-controlled genes or CCGs) to provide approaches for (i) treating diseases or enhancing or modifying body functions or activities related to under- or over-expression of such proteins, for example in cancers, leukemias, or other proliferative or malignant diseases; and (ii) enhancing the immune system and/or influence cell self-renewal, proliferation, differentiation, activity, longevity, function, and/or potency (paragraphs [0013], [0029] and [0077] to [0081]). They teach that the molecular control mechanism utilized in the circadian clock system is the presence in the upstream or regulatory regions of CCGs an element designated as an E-box and that CCGs are directly transcriptionally regulated by clock components or regulators (paragraphs [0029] and [0030]).
Wu et al. teaches nucleic acid sequences of known circadian transcriptional regulators include: CLOCK (see GenBank Accession NM —152221 (human) and NW 000231 (mouse)); BMAL1 (see GenBank Accession NM—001178 (human) and NW—000332 (mouse)); PER1 (see GenBank Accession NM—002616 (human) and AF223952 (mouse)); PER2 (see GenBank Accession NM—022817 and NM—003894 (human) and NM—011066 (mouse)); PER3 (see GenBank Accession NM—016831 (human) and XM—124453 (mouse)); CRY1 (see GenBank Accession NM—004075 (human) and NM—007771 (mouse)); and CRY2 (see GenBank Accession XM—051030 (human) and XM—130307 (mouse)) (paragraph [0039]). They teach that these transcriptional regulators can be positive or negative regulators where the positive regulators (promoters) are CLOCK and BMAL1 while the negative regulators (repressors) are PER1, PER2, PER3, CRY1 and CRY2 (paragraph [0032]). They also teach that some CCGs are regulated directly by CLOCK and BMAL1 heterodimers interacting through the E-box nucleic acid sequence (CACGTG; SEQ ID No: 2) in these genes (paragraph [0149]).
Wu et al. further teaches that mammalian cells can be transformed using adenovirus vectors or retroviral vectors for heterologous expression of a protein or polypeptide wherein modified retroviral vectors can form infective transformation systems, i.e. viral particles comprising the viral vectors encoding protein of interest can be formed, to deliver nucleic acid encoding the desired positive or negative regulator and/or other heterologous proteins into a target cell (paragraphs [0063] and [0064]). They teach that in vivo therapies can include administration of in vitro transfected cells to an individual for modulating the circadian clock system of the cells using either positive or negative regulators that are expressed therein (paragraphs [0055] and [0066]).
Wu et al. further specifically teaches construction of a Per1-luciferase reporter plasmid which comprises a 7.2 kb fragment of the promoter region from mper1 (mouse Per1; forming the vector named pGL3-mPer1-7.2 kb) and the transfection of said plasmid into NIH 3T3 cells where transcriptional activity was induced and monitored (paragraphs [0028], [00178] to [00180] and Fig. 14). Hence, Wu et al. teaches a recombinant nucleic acid molecule comprising the transcriptional regulatory nucleic acid sequence of mper1, which is a circadian-responsive gene that is a repressor region, that is operably linked to the nucleic acid sequence encoding luciferase, a reporter gene/protein. Wu et al. teaches that in cells having a circadian clock system, CCGs include IL-12 (GenBank Accession U89323), TGF-β1, TGF-β2 and TGF-β3 (paragraphs [0013] and [0073]). They teach that these CCGs contain E-boxes in their regulatory regions (paragraph [0073]).
Wu et al. does not specifically teach a recombinant nucleic acid molecule comprising at least one transcriptional regulatory nucleic acid sequence of a circadian-responsive gene operably linked to a nucleic acid sequence encoding a therapeutic biologic.
However, these deficiencies are made up in the teachings of Wu et al., Jacobsen et al., Del Vecchio et al. and Kuo and Ladurner.
As taught by Jacobsen et al., IL-12 of Wu et al. is a growth factor for hematopoietic stem cells and their myeloid progeny (Title and Abstract). Moreover, as taught by Del Vecchio et al., IL-12 has clinical applications as a therapeutic biologic in cancer patients (Title and Abstract).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of generating a recombinant nucleic acid molecule comprising the transcriptional regulatory nucleic acid sequence of a circadian-responsive gene of the promoter region of mper1 operably linked to a nucleic acid sequence encoding luciferase as taught by Wu et al. and replacing the nucleic acid sequence encoding luciferase as taught by Wu et al. with the nucleic acid sequence encoding IL-12 which is a therapeutic biologic/protein as taught by Wu et al., Jacobsen et al. and Del Vecchio et al. because Wu et al. teaches that by transfecting a target cell with said recombinant nucleic acid molecule, a method to modulate the said target cell can be achieved to regulate the timing of the expression of the encoded protein of IL-12 that matches the natural circadian rhythm for disease treatment. The motivation to align expression of a therapeutic biologic to the patient’s circadian rhythm would be to achieve “time-based automated drug delivery/administration” or “chrono-based drug delivery/administration” from within the cell because Kuo and Ladurner teaches that cancer chronotherapy can provide optimized efficacy based on the physiological link between the therapeutic agent and the molecular processes that respond to the agent at the cellular and organismic level (Pg 4 column right second full paragraph). This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (second)
Claims 1-9 and 24- 29 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (US20030180947A1 Date Published 2003-09-25), Jacobsen et al. (J Exp Med. 1993 Aug 1;178(2):413-8), Del Vecchio et al. (Clin Cancer Res (2007) 13 (16): 4677–4685) and Kuo and Ladurner (Front Genet. 2020 Jun 19;11:601) as applied to claims 1-6 and 24- 29 above and further in view of Cox and Takahashi (J Mol Endocrinol 2019 Nov;63(4):R93-R102; cited in instant specification Pg 7).
The teachings of Wu et al., Jacobsen et al., Del Vecchio et al. and Kuo and Ladurner have already been described in the first 103 rejection above as applied to claims 1-6, 24-27 and 29.
Wu et al., Jacobsen et al., Del Vecchio et al. and Kuo and Ladurner do not specifically teach the nucleic acid molecule of instant claim 1, wherein the transcriptional regulatory region comprises one or more ROR response elements; or one or more RRE elements; or one or more D-box elements upon which DBP and NFIL3 dimers bind.
These deficiencies are made up by the teachings of Cox and Takahashi.
Cox and Takahashi teach the mammalian circadian clock genes and the transcriptional architecture of the clock mechanism have evolved to maintain cellular activities to be in synchrony with the activities of the organism (Title and Abstract). They teach in Figure 1 components of the mammalian circadian clock which describes three feedback loops in the system, namely CLOCK/BMAL1, ROR/REV-ERB, and DBP/NFIL3. They also teach that retinoic acid-related orphan receptors (RORα, RORβ, and RORγ) bind to RRE elements on the BMAL1 gene promoter to provide positive regulation of BMAL1 transcription (Figure 1). They further teach in Figure 1 that DBP and NFIL3 dimerize and bind to D-box elements on the promoters of many core clock genes to provide additional layers of regulation of the mammalian circadian clock.
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of generating a recombinant nucleic acid molecule as taught by Wu et al. Jacobsen et al. and Del Vecchio et al. as described in the first 103 above and substituting the transcriptional regulatory nucleic acid sequence of mper1 as taught by Wu et al. with that of ROR, RRE or D-box elements upon which DBP and NFIL3 binds as taught by Cox and Takahashi because Cox and Takahashi teaches these elements are present in the mammalian circadian clock and have evolved to orchestrate and regulate the transcription of a large network of clock-controlled genes. As such, one of ordinary skill in the art would be able to design and generate a recombinant nucleic acid with the desired regulatory characteristics using the transcriptional regulatory nucleic acid sequence of choice based on their known function in the circadian clock system as taught by Cox and Takahashi. This is an example of (B) Simple substitution of one known element for another to obtain predictable results. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (third)
Claims 1-6 and 24-30 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (US20030180947A1 Date Published 2003-09-25), Jacobsen et al. (J Exp Med. 1993 Aug 1;178(2):413-8), Del Vecchio et al. (Clin Cancer Res (2007) 13 (16): 4677–4685), Kuo and Ladurner (Front Genet. 2020 Jun 19;11:601) as applied to claims 1-6 and 24- 29 above and further in view of Gouze et al. (Arthritis Res Ther. 2003;5(5):R301-9) and Gibbs and Ray (Arthritis Res Ther. 2013 Feb 21;15(1):205).
The teachings of Wu et al., Jacobsen et al., Del Vecchio et al. and Kuo and Ladurner have already been described in the first 103 rejection above as applied to claims 1-6, 24-27 and 29.
Wu et al., Jacobsen et al., Del Vecchio et al. and Kuo and Ladurner do not specifically teach the nucleic acid construct or vector of instant claim 26 comprising a Per2 promoter and the therapeutic biologic is an IL-1 receptor antagonist (IL-1Ra).
These deficiencies are made up by the teachings Gouze et al. and Gibbs and Ray.
Gouze et al. teaches the recombinant form of IL-1 receptor antagonist (IL-1Ra), anakinra, has been approved for clinical use in the treatment of rheumatoid arthritis (Abstract). They teach that anakinra must be administered daily by subcutaneous injection and as such gene transfer of IL-1Ra may offer a more effective means of delivery (Abstract). To this end, Gouze et al. teach that HIG-82 cells were genetically modified by gene transfer to constitutively express IL-1Ra to inhibit the biologic actions of IL-1β. They teach that upon challenge with IL-1 β, constitutive synthesis of IL-1Ra by the genetically modified cells provided sustained or increased protection from IL-1 stimulation compared to cells that were incubated with a range of recombinant anakinra doses where in fact recombinant protein became progressively less effective over time (Abstract).
As described in the first 103 rejection above, Wu et al. teaches the negative regulator of PER2 (see GenBank Accession NM—022817 and NM—003894 (human) and NM—011066 (mouse); paragraphs [0032] and [0039]).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of generating a recombinant nucleic acid molecule comprising the transcriptional regulatory nucleic acid sequence of a circadian-responsive gene of the promoter region of mper1 as taught by Wu et al. operably linked the nucleic acid sequence encoding IL-12 which is a therapeutic biologic/protein as taught by Wu et al., Jacobsen et al. and Del Vecchio et al., and substituting the promoter region of mper1 of Wu et al. with PER2 promoter also as taught by Wu et al., and further substituting IL-12 taught by Wu et al. with IL-1Ra as taught by Gauze et al. as the therapeutic biologic because Gauze et al. teaches that constitutive expression of IL-1Ra by genetically modified cells provided sustained protection from IL-1 in a rheumatoid arthritis model. The motivation to generate cells that can express therapeutic IL-1Ra constitutively while under the modulation of circadian-responsive genes would be the advantage of producing therapeutic concentrations of IL-1Ra based on the molecular clock or circadian rhythm because Gibbs and Ray teaches that rheumatoid arthritis exhibits diurnal variation in symptoms, with patients suffering increased painful joint stiffness in the early morning and that the temporal variation in disease pathology is directed by the circadian clock, at a systemic level through the central clock, and at a local level by autonomous clocks found within inflammatory organs and cells (Abstract). This is an example of (B) Simple substitution of one known element for another to obtain predictable results; (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103 (fourth)
Claims 1-6, 24-29, 31 and 63-64 are rejected under 35 U.S.C. 103 as being unpatentable over Wu et al. (US20030180947A1 Date Published 2003-09-25), Jacobsen et al. (J Exp Med. 1993 Aug 1;178(2):413-8), Del Vecchio et al. (Clin Cancer Res (2007) 13 (16): 4677–4685), Kuo and Ladurner (Front Genet. 2020 Jun 19;11:601) as applied to claims 1-6 and 24-29 above and further in view of Zhou and Bullock (US20030235535A1 Date Published 2003-12-25).
The teachings of Wu et al., Jacobsen et al., Del Vecchio et al. and Kuo and Ladurner have already been described in the first 103 rejection above as applied to claims 1-6, 24- 29.
Wu et al., Jacobsen et al., Del Vecchio et al. and Kuo and Ladurner do not specifically teach a genetically modified cell comprising a heterologous nucleic acid sequence incorporated into its genome, wherein the heterologous nucleic acid sequence comprises the nucleic acid molecule of instant claim 1.
They also do not specifically teach a method of treating a condition, disease or disorder in a subject in need thereof, the method comprising administering an effective amount of a composition comprising the genetically modified cell of instant claim 31; or wherein the condition, disease or disorder is a cancer or other diseases as recited in instant claim 64.
These deficiencies are made up by the teachings of Zhou and Bullock.
Zhou and Bullock teach a method for modulating circadian rhythm of an animal and isolated nucleic acid comprising a PK2 gene promoter operatively linked to a heterologous nucleotide sequence (Abstract). They teach in FIG. 2 that the PK2 gene comprises E-box sequences. They also teach that a nucleic acid containing a PK2 gene promoter operatively linked to a heterologous nucleotide sequence can be delivered into a mammalian cell, either in vivo or in vitro using suitable vectors that include viral vectors such as retroviral vectors, adenovirus, adeno-associated virus, lentivirus, herpesvirus, as well as non-viral vectors such as plasmid vectors (paragraphs [0085] and [0086]). They further teach cells containing said isolated nucleic acid molecule can be incorporated into the host cell genome (paragraph [0168]).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the combined method of generating a recombinant nucleic acid molecule as taught by Wu et al. Jacobsen et al. and Del Vecchio et al. that can be delivered into a mammalian cell and become incorporated into the host cell genome using suitable vectors as taught by Zhou and Bullock because of the advantages of having stable integration of the recombinant nucleic acid molecule in the host cell genome that would ensure long-term, permanent transgene expression that gets replicated along with the host chromosomes during cell division.
In addition, one of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method of treating a condition, disease or disorder in a subject in need thereof, the method comprising administering an effective amount of a composition comprising the genetically modified cell generated by performing the said combined method of Wu et al., Jacobsen et al., Del Vecchio and Zhou and Bullock described in the paragraph above, because Wu et al. teaches that administration to an individual of transfected cells that comprise recombinant nucleic acid sequences comprising circadian-responsive gene(s) linked to a therapeutic biologic, is a possible method for in vivo therapy or treatment of diseases including cancer. This is an example of (A) Combining prior art elements according to known methods to yield predictable results; and (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Yie-Chia Lee (Tonya) whose telephone number is (571)272-0123. The examiner can normally be reached Monday - Friday 7.30a - 3.30p Eastern Time Zone.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642
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