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 .
Application Status
The preliminary amendment filed October 27, 2023 is acknowledged. Claims 1-27 are pending and under examination.
Drawings
The drawings are objected to because they were submitted in color, but there is no granted petition to accept color drawings. See 37 CFR 1.84(a)(2) (“The Office will accept color drawings in utility patent applications only after granting a petition filed under this paragraph explaining why the color drawings are necessary”). Applicants must either provide that explanation via a petition and comply with all requirements of 37 CFR 1.84(a)(2)(i)-(iii) OR submit replacement sheets in black and white and include a clear instruction to replace the color drawings with the replacement sheets. The examiner takes no position on whether color drawings are necessary as the only practical medium by which to disclose the subject matter sought to be patented in this utility patent application.
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.
Specification
The use of the term CellTrace®, CellRox® and Gel-Code®, which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Rejections - 35 USC § 112(d)
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.
Claims 5 and 22 are 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 5 recites “The method of claim 4, wherein the double-stranded RNA is a small interfering RNA.” Although the Specification doesn’t define small interfering RNAs (siRNAs), they are well-known in the art as comprised of a short, 20-23 nt linear, non-hairpined double-stranded RNA. Claim 4 depends from claim 3 and recites “wherein the double-stranded RNA is selected from the group consisting of small temporal RNA (stRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), short hairpin RNA (shRNA) or microRNA (miRNA).” Although all of the dsRNAs recited in claim 4 are involved in RNAi, none of them are equivalent to an siRNA are a larger genus encompassing siRNAs. Therefore, claim 5 does not include all the limitations of claim 4 from which it depends.
It is suggested that claim 5 depend directly from claim 3, or be amended to recite one of the options in the Markush group in claim 4.
Claim 22 recites “The composition of claim 21, wherein the double-stranded RNA is a small interfering RNA.” Although the Specification doesn’t define small interfering RNAs (siRNAs), they are well-known in the art as comprised of a short, 20-23 nt linear piece of non-hairpin double-stranded RNA. Claim 21 depends from claim 20 and recites “wherein the double-stranded RNA is selected from the group consisting of small temporal RNA (stRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), short hairpin RNA (shRNA) or microRNA (miRNA).” Although all of the dsRNAs recited in claim 21 are involved in RNAi, none of them are equivalent to an siRNA are a larger genus encompassing siRNAs. Therefore, claim 22 does not include all the limitations of claim 21 from which it depends.
It is suggested that claim 22 depend directly from claim 20, or be amended to recite one of the options in the Markush group in claim 21.
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 § 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 3-5 and 20-22 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 3 and 20 recite “wherein the nucleic acid molecule comprises a dsRNA effective for inhibiting or decreasing the expression of Wdr37.” The grammar of claims 3 and 20 renders them indefinite. There are two mutually exclusive ways to interpret the sentences of claims 3 and 20. The first interpretation is “inhibiting the expression of Wdr37 or decreasing the expression of Wdr37”, which limits the effect of the composition to modulating the expression of the protein. The second interpretation is “inhibiting Wdr37 or decreasing the expression of Wdr37”, which is broader and encompasses a nucleic acid that is effective at inhibiting the activity of the Wdr37 protein. Given that claim 1 includes means of inhibiting Wdr37 expression or protein activity, both of these interpretations are reasonable; however, they are mutually exclusive rendering the claims indefinite.
Claims 4-5 and 21-22 are rejected for depending from claims 3 and 20, respectively, and not remedying the indefiniteness.
If Applicant intends for claims 3-5 and 20-22 to be limited to dsRNA inhibitors whose function is limited to modulating the expression of Wdr37, the following claim language for claims 3 and 20 is suggested: wherein the nucleic acid molecule comprises a dsRNA that is effective for decreasing the expression of Wdr37.”
Claim Rejections - 35 USC § 112(a) – Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A3.(a).(i) states, “whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
For claims drawn to a genus, MPEP 2163.II.A3.(a).(ii) states, “written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species” where “representative number of species' means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.”
Claim 1 and 27 recite “a composition effective for modulating Wdr37 … comprising decreasing Wdr37 gene expression, decreasing Wdr37 protein expression, decreasing Wdr37 activity, or any combination thereof”. Claim 17 recites “A composition comprising at least one inhibitor of Wdr37”. Therefore claims 1, 17 and 27 encompass a composition comprising virtually any chemical/molecule or combination of chemical/molecules that must have the function of inhibiting Wdr27 gene expression, protein expression, or protein activity. For the reasons described below, Applicant has not sufficiently described the genus of “compositions” that have the recited function.
Size and diversity of genus
Claims 1, 17 and 27 include a genus of compositions comprising virtually any chemical/molecule or combination of chemical/molecules, which can include protein binding partners, antibodies, small molecules, cations, anions, metallic ions, dissolved gasses, nucleic acids, sugars, carbohydrates, lipids and steroids. Each of these sub-genera is extremely diverse. For instance, a genus of short-inhibitory peptides of 20 amino acids would consist of 2020 = 1026 different peptides. Additionally, the composition could include inhibitors of proteins that act “upstream or downstream of the Wdr37 signaling cascade” (Specification [0043]), which includes additional targets of each of the chemicals/molecules. As such, the genus of “compositions” seems to include virtually any chemical or molecule, which is extremely large, possibly limitless, and extremely diverse.
Guidance in the Specification
The Specification generically describes inhibitors of Wdr37 gene expression, protein expression and protein activity as being “biomolecules” including peptides, antibodies, chemicals, compounds, oligos, nucleic acids” ([0042]) and modulators of upstream and downstream proteins/genes ([0048]). The Specification describes sub-genera, for example, dsRNA as a sub-genera of nucleic acid inhibitors ([0046]). However, other than dsRNA that specifically targets the Wdr37 RNA, the Specification does not indicate what other genes the dsRNA should target. Likewise, the Specification teaches that CRISPR nucleases can be targeted to DNA for genome editing ([0050]); but other than the Wdr37 gene itself, the Specification does not indicate what other gene to target. The Specification does not actually disclose any means to inhibit Wdr37 other than to create a knockout mouse using CRISPR/Cas9 targeted to exon 4 of the Wdr37 gene ([0124]), but does not disclose the sequence of the guide RNA used to create the 2-bp frame shift, Wdr37-null allele. The Specification does not list a single species of any molecule that can modulate the activity of the Wdr37 protein. The Specification also does not provide any protein binding partner other than Pacs1, that can modulate Wdr37 activity. Therefore, other than Pacs1, it is completely unpredictable what other genes may lie “upstream or downstream” that can be targeted modulate the activity or expression of Wdr37. Therefore, the Specification only describes a single species of a composition – Cas9/gRNA targeted to exon 4 of the Wdr37 gene – that has the function of inhibiting Wdr37 gene expression, protein expression, or protein activity
As a whole, the Specification does not sufficiently describe the genus of compositions that have the claimed function of modulating Wdr37.
Guidance in the Prior Art
Zender teaches an Wdr37-targeting shRNA-encoding lentiviral vector that is effective at decreasing expression of Wdr37 (US 20100273660 A1; [0266], [0272], Tables 1-2). Although Zender does not disclose the sequence of the shRNA-targeting Wdr37, Zender does teach that methods to design shRNAs and siRNAs are generally known in the art ([0181]).
Wan teaches that Ash2l binds to the Wdr37 gene (Wan et al., Journal of Biological Chemistry (2013), 288: 5039-5048; Fig 3). Although Wan concludes that Ash2l generally promotes an open chromatin state that is associated with increased transcription (Fig 3), Wan does not disclose whether Ash2l-binding has any effect on Wdr37 gene expression.
Wdr37 is known to physically interact with a variety of proteins, including PACS1, PACS2 and CCT4 (Huttlin et al., Nature (2017), 545: 505-509; Extended data 1). However, Huttlin does not describe whether these protein interactions are stabilizing, destabilizing, or neither.
Saito teaches that the protein BAFF expression results in downregulation of Wdr37 expression during B cell development (Saito et al., Immunology (2008), 125: 570-590). As such Saito provides for a single protein that can act in a composition to decrease Wdr37 expression.
Santa Cruz Biotechnology lists 11 small molecule inhibitors as “potential” Wdr37 inhibitors (WDR37 inhibitors, https://www.scbt.com/browse/wdr37-inhibitors, [retrieved February 19, 2026]). However, all of the potential inhibitors are known to affect other pathways like the mTOR, ubiquitin, or PI3K. It does not appear that any of the listed compounds directly inhibit Wdr37, and it is unverified if Wdr37 is actually a component of the listed pathways.
Reis teaches that Specific missense alleles cause a potentially dominant severe multisystemic syndrome (Reis et al., American Journal of Human Genetics (2019) 105: 425-433; Abstract). Reis characterizes Wdr37 as a 494-amino acid protein of unknown function (Abstract; page 428). Reis adds 1) “WD40 repeat domain represent a common protein interaction domain in humans, generally mediates interactions with other proteins” (page 432, ¶4). Reis’s results in zebrafish “suggest that Wdr37 may play a role in cholesterol biosynthesis”, but that “further work is needed to determine how Wdr37 interacts with the cholesterol pathway” (page 432, ¶4). Thus, Reis supports the conclusion that it was not known what other genes/proteins/pathways to inhibit that would in turn modulate the activity or expression of Wdr37.
Finally, various companies sell polyclonal antibodies targeted to the Wdr37 protein (see e.g., Millipore Sigma, Anti-WDR37 antibody produced in rabbit, https://www.sigmaaldrich.com/US/en/product/sigma/hpa037376, [retrieved February 23, 2026])). However, in each case the Wdr37 antibody has only been verified for immunohistochemistry, immunofluorescence, and/or immunoblot applications. There is no evidence in the art that any of the antibodies are functional in vitro or in vivo at inhibiting the activity of the Wdr37 protein.
Only two means for modulating expression of Wdr37 – RNAi based interference of the Wdr37 RNA and BAFF treatment – have been demonstrated in the prior art. Based on Reis’s characterization of Wdr37 as having an unknown function, other means and compositions for inhibiting Wdr37 function were not predictable at the effective filing date of the claimed invention.
Given the extremely vast and diverse genus of the claimed compositions, a lack of working examples in the Specification of compositions that can modulate Wdr37 expression and activity, the lack of Wdr37-modulating compositions in the prior art, and the general lack of understanding in the art about the function of Wdr37 in various cells types including lymphoid cells, the skilled artisan would reasonably conclude that Applicant did not possess the genus of “compositions effective for modulating Wdr37” as claimed.
Claims 2, 6-16, 18-19 and 23-26 do not limit the genus of “compositions”, and therefore are not sufficiently described for the reasons recited above for claims 1 and 17.
Claims 3-5 and 20-22 require that inhibitor of Wdr37 comprises a nucleic acid molecule comprising dsRNA, which include the known RNAi modalities shRNAs and shRNAs. However, the claims still encompass targeting the inhibitory dsRNAs to genes other than Wdr37. Because the function and regulation of Wdr37 is largely unknown and it is not predictable which genes, other than Wdr37 itself, the skilled artisan should target to modulate the expression and/or activity of Wdr37, the genus of dsRNA-based inhibitors is still insufficiently described.
Claims 4 and 21 recite the dsRNA is a small temporal RNA (stRNA), small nuclear RNA (snRNA) and small nucleolar RNA (snoRNA). StRNAs appear to be a subset of naturally occurring miRNAs that are temporarily activated during animal development (See e.g., Sokol, Current Opinion in Genetics and Development (2012), 22: 368-373). Thus, although stRNAs are dsRNA species, it is completely unknown how to design a dsRNA to a target such that it would be considered an stRNA and not generally a miRNA. SnRNAs are short, noncoding RNAs of ~ 150 nucleotides that associate with proteins to form snRNPs, which function primarily in pre-mRNA splicing (see Blog post: Small nuclear RNAs: biogenesis, function, and NGS-based study techniques, https://www.revvity.com/blog/small-nuclear-rnas-biogenesis-function-and-ngs-based-study-techniques, [retrieved February 23, 2026]). Although the Wdr37 pre-mRNA has introns, it is not clear how administering a snRNA would in any way change the expression level of Wdr37. Administering snRNAs to affect pre-mRNA splicing is not a typical means for regulating genes at the transcriptional or post-transcriptional level. SnoRNAs are non-coding RNAs involved in rRNA and snRNA processing (See e.g., Bratkovič and Rogelj, Cellular and Molecular Life Sciences (2011), 68: 3843-3851). It is not clear how administering a snoRNA would in any way change the expression level of Wdr37 since snoRNAs do not directly impact Wdr37 RNA metabolism. Thus, it is not understood how the skilled artisan would design an stRNA, snRNA or snoRNA such that it would modulate Wdr37 expression and/or function.
Claim Rejections - 35 USC § 112 - Enablement
Claims 1-16 and 23-26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Exemplary factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 737, 8 U.S.P.Q.2d 1400, 1404 (Fed. Cir. 1988) (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP 2164.01(a). All of these factors were considered, along with others, and a sufficient number are addressed below so as to create a prima facie case.
Nature of the Invention and Breadth of Claims
Claims 1 and 23 are drawn to methods for attenuating, treating or preventing at least one lymphoproliferative disease [or at least one lymphoid malignancy] by administering to the subject a composition effective for inhibiting Wdr37 expression and/or activity. As indicated above in the rejection for lack of written description, the genus of “compositions effective for modulating or inhibiting Wdr37 expression and/or activity” is not sufficiently described. For the purposes of this enablement rejection, the analysis will focus on the predictability of treating and preventing lymphoproliferative diseases and lymphoid malignancies using compositions comprising 1) dsRNA inhibitors targeted to Wdr37 coding region and 2) a gene editing system such as Cas9/gRNA targeted to the Wdr37 locus, for which there is sufficient written description.
The genus of lymphoproliferative diseases and/or lymphoid malignancies includes those diseases listed in claims 9 and 13 and include proliferation of any lymphoid cells or tissues including, T cell lineages, B cell lineages, Natural Killer cells, and Innate Lymphoid cells (ILCs). “Prevention” is interpreted as preventing any genetic, metabolic or cellular change that leads to the formation lymphoid proliferation diseases including chromosomal translocations, chromosomal amplifications and dysregulated signaling pathways. See e.g., Shaffer et al., Annu. Rev. Immunol. (2012), 30: 565-610. “Attenuation” and “treating” is interpreted as decreasing the proliferative capacity of lymphoid cells and/or reducing the symptoms associated with the diseases.
Accordingly, enablement of the method requires one skilled in the art to be able to prevent genetic modifications and/or signaling dysregulation leading to the genus of lymphoid proliferative diseases and decreasing the proliferative capacity of lymphoid cells and/or reducing the symptoms associated with the diseases using a Wdr37-targeted RNAi inhibitor or gene editing system.
Guidance in the Specification
Applicant provides a set of elegant studies that progresses the understanding of Pacs1 and Wdr37 in the Calcium-dependent signaling during lymphocyte activation. Applicant shows that Pacs1 knockout mice have a deficiency in circulating B and T cells, demonstrating the requirement for Pacs1 in lymphocyte development ([0109]), likely through regulating Ca++ efflux from subcellular compartments ([0133]-[0116]). Pacs1 deletion causes increased Ca++ leakage from the ER and reduced stimulated ER Ca++ release ([0134]-[0136]). Applicant also shows that the Wdr37 protein binds to and stabilizes Pacs1 and that Wdr37 null mice had reduced numbers of lymphocytes ([0121]-[0125]). Applicant demonstrates that Pacs1-null B cells have normal proliferative capacity in vitro, are functional in vivo, but have reduced life upon activation in some environments ([0138]-[0142]). Finally, Applicant shows that Pacs1-null cells have reduced proliferative capacity in mouse models of lymphoproliferation ([0143]-[0147]). Specifically, eliminating Pacs1 protein expression in mice that either overexpress the anti-apoptotic protein, Bcl2, or are deficient in Fas pro-apoptotic signaling showed higher sensitivity to cell death stimuli ([0143]-[0147]), suggesting that disrupting Pacs1 stabilization in vivo could suppress lymphoproliferative diseases in B and T cell lineages ([0146]).
The working examples in the Specification do not actually administer any Pacs1 inhibitor or Wdr37 inhibitor to the mice models having lymphoproliferative diseases. The Specification also doesn’t disclose inhibiting Wdr37 in any manner (knockout, RNAi, or otherwise) in the mice models having lymphoproliferative diseases. The Specification also provides no guidance as to how one would prevent lymphoid diseases from occurring, especially those that are caused by chromosomal translocations and amplifications.
Accordingly, in light of the specification, it is highly unpredictable if one skilled in the art could administer a Wdr37 inhibiting RNAi or gene editing system to prevent the claimed diseases or ameliorate symptoms of the diseases.
State of the Prior Art
As indicated above in the rejections for lack of written description, Wdr37 is a relatively uncharacterized protein. Zender teaches an Wdr37-targeting shRNA-encoding lentiviral vector that is effective at decreasing expression of Wdr37 (US 20100273660 A1; [0266], [0272], Tables 1-2). However, Zender characterizes Wdr37 as a “tumor suppressor gene” ([0057]). When expression of Wdr37 is reduced by administering a Wdr37-targeted shRNA to a hepatocellular carcinoma (HCC) cells (i.e., a liver cancer cells), the proliferative capacity of the cells increased ([0272]-[0273]; Tables 1-2). This suggests that at least in liver cancer cells, inhibiting Wdr37 expression and/or activity increases the proliferative capacity of cells.
Saito investigated the molecular and genetic consequences of pro-cell-survival BAFF signaling in B cells (Saito et al., Immunology (2008), 125: 570-590). BAFF-mediated B-cell stimulation inhibits apoptosis in B cells by inducing CD20-mediated and BCR-mediated signaling (page 571, ¶4). Interestingly, BAFF-signaling resulted in downregulation of Wdr37 expression during B cell development (Table 2). This suggests that decreased Wdr37 expression is correlated with B cell proliferation and survival. As such, inhibiting the expression of Wdr37 would not be predicted to reduce B cell proliferation or result in amelioration of lymphoproliferation.
Wdr37 is known to physically interact with a variety of proteins (Huttlin et al., Nature (2017), 545: 505-509; Extended data 1), a few of which are known to be associated with lymphomas. For instance, increased TCP-1 expression is correlated with increased incidence of lymphoma lymphatic metastasis (Jiang et al., Oncotarget (2015), 6: 42105-42117). However, Huttlin does not describe whether these protein interactions are stabilizing, destabilizing or neither. So, it is not clear from Huttlin if inhibiting Wdr37 would likewise inhibit TCP-1 expression or function.
A thorough search of the prior art found no teaching of delivering Wdr37-targeted RNAi agents or gene editing systems specifically to lymphoid cells or cells of a lymphoproliferation diseases to determine the effects of downregulating Wdr37 in those tissues. As such, it is unknown what the effect of inhibiting the expression of Wdr37 would have on its many protein binding partners and apoptotic or cell-survival pathways. Finally, there are no teachings in the prior art that Wdr37 has any function in the nucleus where it might influence DNA repair networks such that inhibiting the protein would be predicted to prevent lymphoproliferation diseases from occurring in the first place.
Thus, in view of the prior art, it is highly unpredictable if or how one skilled in the art could administer a Wdr37 inhibiting RNAi or gene editing system to prevent the claimed diseases or ameliorate symptoms of the diseases.
Experimentation Required
In order to practice the invention, one skilled in the art would need to design Wdr37 RNAi and/or gene editing systems to reduce expression in hematopoietic, lymphoid-progenitor, and lymphoid cells to determine the effect of Wdr37 inhibition. Then the inhibitor studies would need to be recapitulated in mouse and primate models of each disease, and finally clinical trials. However, given the great unpredictability in the art regarding the role of the Wdr37 in apoptotic or cell-survival signaling networks, it is highly unpredictable whether such inhibitors would have any effect.
Conclusion
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant, and the lack of working examples of inhibiting expression of Wdr37 in a model of lymphoproliferative diseases, it is the conclusion that undue experimentation would be required to make and use the invention.
Dependent claims
Claims 2-14 and 24 do not limit the lymphoproliferative disease, do not recite a disease in which the function of Wdr37 is characterized, or do not recite a disease in which the effect of inhibiting Wdr37 is known. Thus, for the reasons recited above for claims 1 and 23, it is the conclusion that an undue experimentation would be required to make and use the invention.
Claims 15-16 recite the patients are undergoing therapy or have already undergone therapy for treatment of a lymphoproliferation diseases. These claims also lack enablement because there is no evidence in the art that the treatments recited in claim 16 can prevent the disease in the first place. Additionally, the claims do not recite administering the therapy and include instances where the subject has already undergone the therapy. Thus, there is no requirement for administration of an already proven therapy.
Claims 25-26 recite administering to the subjects an effective amount of a therapy for lymphoproliferation. These claims also lack enablement because there is no evidence in the art that the treatments recited in claim 26 can prevent the disease in the first place.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 17-21 and 27 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zender (US 20100273660 A1, published October 28, 2010).
Regarding claims 17, Zender teaches a library (i.e., a composition) of shRNAmirs (i.e., gene expression inhibitors) targeting genes proposed to be associated with hepatocellular carcinoma ([0266]). Zender teaches preparing the shRNAmir library carried by a lentiviral vector (i.e., a pharmaceutically acceptable carrier) for delivery to liver progenitor cells ([0266], [0272]). Zender teaches on of the shRNAmirs targeting Wdr37 (Tables 1-2). Therefore, Zender teaches a composition comprising at least one inhibitor of Wdr37and a pharmaceutically acceptable carrier.
Regarding claim 18, Zender teaches the lentiviral vectors with the shRNAmirs were performed using packaging cells (i.e., the lentiviral vectors comprising the shRNAs were in a viral supernatant, which is encompassed by a pharmaceutically acceptable excipient) ([0304]).
Regarding claim 19-21, Zender teaches Wdr37-targeting shRNA (i.e., a short hairpin RNA, which is a dsRNA nucleic acid inhibitor that decreases expression of WDR37) (Tables 1-2).
Regarding claim 27, the specification does not provide a special definition for the term "kit”, thus "kit" is interpreted as merely the sum of its contents. As recited above for claim 17, Zender teaches an shRNA lentiviral vector library comprising a Wdr37-targeting shRNA (i.e., a composition effective for decreasing expression of WDR37) ([0266]; Tables 1-2). Zender teaches the lentiviral vectors with the shRNAmirs were performed using packaging cells ([0304]). The tissue culture dish with the packaging cells is a container.
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.
Claim 22 is rejected under 35 U.S.C. 103 as being unpatentable over Zender (US 20100273660 A1, published October 28, 2010).
The teachings of Zender are recited above as for claims 1-21 and 27, which are incorporated here.
Zender does not teach a small interfering RNA (siRNA) targeting Wdr37.
However, Zender also teaches additional dsRNA that are effective at decreasing expression of a target gene include siRNAs ([0018]). Zender teaches siRNAs allow for rapid screening and studying of siRNA sequences and matching genes ([0024]). Zender teaches that siRNAs can be designed using software programs and the general design principles of siRNAs ([0181]).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have designed an siRNA targeting Wdr37. It would have amounted to the simple substitution of on RNA-interfering dsRNA species for another by known means to yield predictable results. The skilled artisan would have predicted that a Wdr37-targeting siRNA could be designed and produced because Zender teaches the siRNA design principles are known and the skilled artisan need only use online software programs. The skilled artisan would have been motivated to do so for the purpose for rapid screening the effects of Wdr37 downregulation in a variety of cell types.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635