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 and Election
Claims 1, 15-16, 23, 27-29, 36, 48 and 86-103 are pending.
Applicant’s election of group I directed to methods of treating decreased serum zinc level, increased serum glucose level, and/or hyperglycemia, and species of GLP-1 agonists and antisense nucleic acid molecules was made without traverse in the reply filed on July 2, 2026. Claim 48 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group, there being no allowable generic or linking claim. In the process of examination, methods of treatment for hyperglycemia with insulin and biguanides were found. Therefore, the genus of therapeutic agents was expanded to include insulin and biguanides in addition to GLP-1 agonists. Claims 94-103 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species, there being no allowable generic or linking claim.
Claims 1, 15-16, 23, 27-29, 36, 86-93 are under examination.
Drawings
The drawings are objected to for three reasons.
First, the drawings 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.
Second, the figures are referred to as "Figure" in the drawings. MPEP §601.V states that according to 37 C.F.R. l.84(u)(l) "View numbers must be preceded by the abbreviation "FIG.".
Third, the partial views of Figure 1A, 1B, 10-13, 15-17, 21-23, 24A, 24B, 25A, 25B, 26A, 26B, 27-28, 30, 31A, 31B, which appear on several sheets, have not been identified by the same number followed by a capital letter. 37 C.F.R. l.84(u)(l) requires that "partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter." For example, sheets 1-4 should be labeled FIG. 1A through FIG. 1D, Figure 1B and 1B (cont) should then be labeled FIG. 1E and FIG. 1F. See MPEP 608.02.
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 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 15-16, 27-29, 36, and 86-93 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.
The term "standard dosage amount" in claims 15, 16 and 27-29 is a relative term which renders the claims indefinite. The term "standard dosage amount" is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Although the specification recites that the therapeutic agents can be reduced by about 10-90% in a heterozygous compared to a wildtype reference individual (page 27, lines 14-25) there is no direction as to what the wildtype reference individual should be given. Additionally, the specification indicates that agents can be given at various time intervals and at the same or different doses (¶ spanning pages 27-28); however, it is still not clear from these teachings what that "standard dosage amount" would be. The only guidance given regarding dosage amounts is for zinc (page 28), which is not one of the recited agents in the dependent claims or claims 15, 16 and 27-29.
The art also does not provide guidance on what a "standard dosage amount" would be. Even the well-known standard hyperglycemia/diabetes drug insulin does not have a "standard dosage amount". A web article from 2020 indicates that although a starting dosage for long-lasting insulin is about 0.2 units for every 2.2 pounds, the dose may go up 2-4 units every 3 days until the individual reaches their fasting blood sugar target, which is in the range of 80 to 130 mg/dl (Linda Rath, What Are Insulin Dosages for Type 2 Diabetes, WebMD (2020), https://web.archive.org/web/20201020065045/https://www.webmd.com/diabetes/diabetes-insulindosages [retrieved October 4, 2023]). Likewise, dosages of Lixisenatide, a GLP-1 agonist, and Metformin, a biguanide, are also titrated to determine the desired effects (Metformin (Oral Route), www.mayoclinic.org/drugs-supplements/metformin-oral-route/proper-use/drg-20067074, [retrieved 2/1/2024]; Lixisenatide (Subcutaneous Route), www.mayoclinic.org/drugssupplements/lixisenatide-subcutaneous-route/proper-use/drg-20312437, [retrieved 2/1/2024]). This indicates that there is no "standard dosage amount" because the dosage amount should be titrated based on an individual's response, which is variable. Given that in the claimed method, the therapeutic agent must also be given in combination with an SLC39A5 inhibitor, which is presumed to also cause a decrease in blood glucose, it would not be clear to the skilled artisan what dose is considered the "standard dosage amount" for any of the agents listed in the claims.
Claims 36 and 86-93 are rejected for depending from claims 15, 16 or 27 and not remedying the indefiniteness.
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, 15-16, 23, 27-29, 36, and 86-93 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, "the 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."
Claims 1 and 27 recite "administering an SLC39A5 inhibitor… wherein the SLC39A5 inhibitor comprises an antibody or an antisense nucleic molecule, an siRNA, an shRNA that hybridizes to an SLC39A5 mRNA.” "SLC39A5 inhibitor" represents a genus of molecules that are defined by their function of inhibiting SLC39A5/Zip5. Regarding nucleic acid-based inhibitors, the genomic and expressed transcript sequences of SLC39A5 are well known (See. e.g., Homo sapiens solute carrier family 39 member 5 (SLC39A5), RefSeqGene on chromosome 12, NCBI Reference Sequence NG_034265.1). Because there is a known correlation between the structure of antisense molecules and their inhibitory function, one skilled in the art could have predicted the structure of antisense and CRISPR guide molecules that have the claimed inhibitor function.
However, for the reasons described below, Applicants have not sufficiently described the genus of SLC59A5 antibodies that have the claimed SLC59A5 inhibitory function such that one skilled in the art could have reasonably concluded applicants had possession of the genus as claimed.
The claims recite an SLC39A5 antibody inhibitor, and therefore only identify the SLC39A5 antibody by function. No SLC39A5 antibody structure is recited that correlates to the claimed function of inhibiting SLC39A5. A definition by function does not suffice to define the genus because it is only an indication of what the SLC39A5 antibody does, rather than what it is. To provide adequate written description and evidence of possession of the claimed SLC39A5 antibody inhibitor genus, the instant specification in view of the art must structurally describe representative SLC39A5 antibodies that function as an inhibitor, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
The specification describes a method to produce SLC39A5/Zip5 antibodies that have the function of reacting with Zip5 when overexpressed in cell culture (Example 18, pages 76-77). However, Applicants do not demonstrate the antibody is capable of inhibiting the function of SLC39A5/Zip5 in culture cells or in vivo when administered to a subject. Applicants disclose that an antibody can bind to a protein with amino acid sequence of SEQ ID NO 22 (page 15), which is the full-length amino acid sequence of Zip5. However, this disclosure speaks to the function of the antibody and not to its structure. The specification also teaches the antibody can comprise amino acid sequences SEQ ID NOs 58, 60 and the complementarity-determining regions (CD Rs) can comprise SEQ ID NOs 62-66 (page 16). The recited sequences are found in numerous antibodies that are not specific for SLC39A5. They do not define enough structure of the variable region for one skilled in the art to predict the rest of the light chain and heavy chain variable region structure that would recognize and possibly inhibit SLC39A5 function. Finally, even if the antibodies were shown to bind to a cell surface exposed region of the SLC39A5 protein in vivo, there is no evidence that the antibody would inhibit the protein’s function. For instance, the only known commercially available therapeutic antibody to a zinc transporter, mAb43 specific to zinc transporter 8 (ZnT8), is only in its preclinical stage and it is thought to function by shielding pancreatic beta cells from immune attacks, and not by specifically inhibiting the function of ZnT8 (Kasinathan et al., Diabetes (2024), 73: 806-818).
A few SLC39A5/Zip5 antibodies are commercially available that can be used to detect Zip5 by western blot, immunofluorescence or immune-histochemistry (e.g., Abcam, Anti-ZIP-5 antibody (ab105194), www.abcam.com/zip-5-antibody-ab105194 [retrieved October 17, 2022]). However, the companies do not provide the structure of the Zip5 antibodies. Additionally, none of the commercially available Zip5 antibodies are disclosed as capable of inhibiting Zip5 function in vivo when administered to a subject.
Although Applicants may argue that it is possible to screen for SLC39A5 antibodies that function as claimed, the court found in that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004. "As we held in Lilly, "[a]n adequate written description of a DNA ... 'requires a precise definition, such as by structure, formula, chemical name, or physical properties,' not a mere wish or plan for obtaining the claimed chemical invention." 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions." Knowledge of screening methods provides no information about the structure of any future SLC39A5 antibody yet to be discovered that may function as an inhibitor as claimed.
Other than the specific amino acids that could be in SLC39A5 antibody, the specification fails to provide the core, critical sequence structure that correlates to the claimed functional characteristics in order for one to recognize members of the claimed genus of SLC39A5 antibodies that function as claimed. The instant specification fails to describe a representative number of SLC39A5 antibody sequences that can inhibit SLC39A5 function when administered to a subject. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Given the lack of representative examples to support the full scope of the SLC39A5 inhibitors encompassed by the claim, and lack of reasonable structure-function correlation with regards to the unknown sequences of SLC39A5 antibodies that provide can inhibit SLC39A5 function, the specification does not provide an adequate written description of molecules that inhibit SLC39A5 function that is required to practice the claimed invention.
Claims 15-16, 23, 28-29, 36 and 86-93 do not limit the genus of SLC39A5 inhibitors and are rejected for the reasons discussed above for claims 1 and 27.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
Claims 1, 15-16, 23, 27-29 and 86-93 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treatment of a female human subject that is wildtype or heterozygous for an SLC39A5 reference allele with an SLC39A5 antisense RNA and insulin, GLP-1 agonists, and biguanides does not reasonably provide enablement for treating all the genus of human subjects that are wildtype or heterozygous for an SLC39A5 reference with an SLC39A5 antisense RNA inhibitor alone or the SLC9A5 inhibitor together with the full genus of claimed therapeutic agents. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
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 2164.0l(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 27 are directed to methods of treating or inhibiting increased serum glucose levels and/or hyperglycemia in a human subject by treating a subject with an SLC39A5 inhibitor when the subject has at least one copy of the SLC39A5 reference allele. Claims 15-16 and 27-29 further include treating with a therapeutic agent. The claims are interpreted as requiring an improvement or prevention of the condition (i.e. treatment or inhibition) of increased serum glucose levels and/or hyperglycemia by treating with a SLC39A5 inhibitor and in some cases additionally a generic therapeutic agent. The genus of SLC39A5 inhibitors includes antibodies or antisense molecules such as shRNA and siRNA. The genus of therapeutic agents that treat or inhibit increased serum glucose and/or hyperglycemia are recited in claims 86 and 90 and includes various classes of known hyperglycemia therapies. However, additional therapeutic agents including PPAR agonists, are also included in the generic recitation of therapeutic agents of claims 1, 15-16 and 27-29. Accordingly, enablement of the method requires one skilled in the art to be able to administer the genus of SCL39A5 inhibitors, and in combination with the genus of therapeutic agents to a subject with increased serum glucose and/or hyperglycemia to bring about a decreased or normal serum glucose level.
Guidance from the Specification
The specification describes possible SLC39A5 inhibitors (pages 15-21) and possible therapeutic agents (pages 26-27); however, the specification does not provide a working example of administering an SLC39A5 inhibitor either alone or in combination with a therapeutic agent to a subject with increased serum glucose that results in the decrease of serum glucose. Instead, the specification provides, by way of example, a method of knocking out the SLC39A5 gene in mice and then assaying the phenotype of the SLC39A5 mice (Examples 4, 6 and 7; pages 70-71). The specification teaches that only female, and not male, SLC39A5 KO mice displayed statistically significant reduction in blood glucose at 12 weeks (page 70, lines 8-9; Figure SB). The specification also teaches that knockout of SLC39A5 resulted in fasting blood glucose reduction in leptin-deficient females, but not males, at 10 and 12 weeks (page 70, lines 25-26; Figure 7B, 7E). In fact, KO of SLC39A5 raised the serum glucose levels of both wildtype and leptin-deficient males (Figure 7E). Thus, from the specification it appears that eliminating the activity of SLC39A5 throughout a subject’s lifetime only reduces blood glucose levels in female mice but not male mice. The SLC39A5 KO female mice in the working examples had no SLC39A5 activity throughout the course of their lifetime. It is not predictable whether a similar reduction in serum glucose levels would result if SLC39A5 activity were inhibited after the female mice develop hyperglycemia, as required by the claimed subject (i.e., a subject having increased serum glucose levels).
The specification also teaches that treating hepatocytic primary cells and cell lines with zinc activates the AMPK and AKT pathways (Fig 24A-B), which are known pathways that induce glucose uptake by cells, thereby lowering blood glucose levels (Nelson and Cox, Lehninger Principles of Biochemistry, 4th Edition (2004), Chapter 23, page 914). However, Applicant fails to determine if this same effect occurs when expression of SCL39A5 is reduced in those cells. SCL39A5/Zip5 is partially responsible for importing zinc into the cells. If zinc import into cells decreases, it is unclear how the cells would respond to the increased extracellular zinc levels and be able to activate the AMPK/AKT pathways.
The specification also fails to provide guidance on inhibitor dosing amounts, timing, or administration routes, for example intravenous, oral, delivery of siRNAs and/or antibodies. The specification also fails to provide guidance on which tissues to target. SLC39A5 is expressed in liver, pancreas and intestine, all of which play a role in regulating the blood glucose levels. Finally, the specification fails to disclose a single working example of treating a SLC39A5 reference or heterozygous mouse with a therapeutic agent with or without an SLC39A5 inhibitor.
Therefore, in light of the specification it is not predictable that administering an SLC39A5 inhibitor alone or in a combination with a therapeutic agent would treat increased serum glucose levels and/or hyperglycemia in a human subject that contains a reference SLC39A5 allele.
State of State of the Prior Art
SLC39A5/Zip5 was previously shown to be involved in serum zinc level regulation through its serosal-to-mucosal transport in the intestine (Wang et al., The Journal of Biological Chemistry (2004), 279(49): 51433-51441; referred to as "Wang1"). More recently SLC39A5/Zip5 was shown to play a role in glucose sensing and insulin secretion in pancreatic beta cells (Wang et al., Protein and Cell (2019), 10(6):436-449; published October 15, 2018; referred to as "Wang2"). As detailed below, Wang2's research suggests that inhibiting SLC39A5 would worsen hyperglycemia, not treat hyperglycemia as required by the claimed method. Furthermore, Wang2's research suggests that SLC39A5 inhibition would counteract or even interfere with known hyperglycemia therapeutic agents like PPAR agonists.
Wang2 teaches that SLC39A5 is consistently down regulated in pancreatic islets in high-fat diet fed mice and leptin-signaling mutant mice (Figure 1). Wang2 also teaches when SLC39A5 is knocked out specifically in beta cells, mice have increased blood sugar levels when measured by a glucose-tolerance test (Figure 2C-D). From these and other results, Wang2 concludes that the function of SLC39A5 in pancreatic beta-cells is to mediate zinc import into beta islet cells, which induces insulin release and promotes the lowering of blood glucose levels (Figure 6). Wang2 also suggests that inhibiting SLC39A5 would disrupt the signaling pathway, thereby inhibiting glucose import into cells and resulting in higher systemic blood glucose levels (Figure 6). Wang2's model would also suggest to one skilled in the art that inhibiting SLC39A5 would have the opposite effect of therapeutic PPAR agonists. Wang2 teaches that SLC39A5-dependent zinc import into beta-cells increases PPAR-y mediated expression of GLUC-2 which is needed to increase glucose transport into cells (i.e., out of serum) (Figure 6). PPAR agonists function to increase PPAR binding to DNA and promote PPAR-mediated expression (Chiarelli and Di Marzio, Vascular Health and Risk Management (2008), 4(2): 297-304; page 297). From Wang's teaching, one skilled in the art would have concluded that decreasing SLC39A5 activity would decrease PPAR-dependent expression of GLUC-2 and increase serum glucose levels, which is the opposite effect to that of a PPAR agonist. Therefore, it was not predictable whether the function of a known "therapeutic agent" for hyperglycemia would have been disrupted when co-administered with an SLC39A5 inhibitor.
Li reports the use of SLC39A5 siRNA to investigate the role of SLC39A5/Zip5 in esophageal cancer in cell cultures and a nude mouse cancer tumor model (Li et al., Oncology Research (2016), 24:205-214). Li uses a lentiviral vector to constitutively express siRNA in an esophageal cancer cell line (Figure 1). However, Li is silent on the effect of SLC395A siRNA on serum glucose levels. Additionally, since the siRNA was only expressed in the esophageal cancerous cells, Li is not predictive of how to administer siRNA systemically or specifically to intestine, liver and/or pancreas where SLC39A5 is normally active.
Thus, in view of the prior art it is not predictable how one skilled in the art would treat elevated serum glucose and/or hyperglycemia using an inhibitor of SLC39A5 in combination with a known hyperglycemia therapy.
Taking into consideration the factors outlined above including 1) Wang2's disclosure suggesting inhibiting SLC39A5 would increase serum glucose levels and may even counteract or interfere with the mechanism of known hyperglycemia therapies; and 2) the lack of working examples of co-administering a therapeutic agent and a SLC39A5 inhibitor to a subject with elevated serum glucose levels to bring about a reduction in serum glucose levels, it is the conclusion that an undue experimentation would be required to use the invention throughout its full scope as claimed.
Dependent claims
Claims 23 and 36 do not limit the genus of subjects or the therapeutic agents and are rejected for the reasons discuss above for claims 1 and 27.
Claims 86-93 limit therapeutic agents that would not predictably interfere/counteract/interact with an SLC39A5 inhibitor or general downregulation of SLC39A5. However, the claims do not limit the genus of subjects. Because there was no apparent effect on male mice with SLC39A5 knockout and in some cases worsened the serum glucose level, it would not have been predictable how the recited therapeutic agent would function along with an SLC39A5 inhibitor in male human subjects.
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 1, 15-16 and 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over Geiser (Geiser et al., PLOS One (2013), 8(11) e82149: 1-11), in view of Wang1 (Wang et al., The Journal of Biological Chemistry (2004), 279(49): 51433-51441) and Jin (Jin et al., Oncology Reports (2015), 34: 1431-1439).
Claims 15-16 and 27-29 are indefinite for the reasons outlined above in paragraphs 12-13. For the purpose of compact prosecution, claims 15-16 and 27-29 are interpreted as administering zinc in any amount to the subjects if the subjects are reference (i.e., wild type) or heterozygous for a loss-of-function allele.
Regarding claim 1, Geiser teaches that the zinc transporter Zip5 is also called SLC39A5 (Title). Geiser teaches Zip5 localizes to the basolateral membrane of intestinal enterocytes, pancreatic acinar cells and embryonic visceral endoderm cells, which play vital roles in zinc homeostasis (page 2, ¶2). Geiser teaches that Zip5 protein is degraded and its production stalled during periods of zinc deficiency (page 2, ¶2). Geiser teaches that knocking out Zip5 in every cell does not produce an overt phenotype indicating that Zip5 is not an essential gene (page 2, ¶4). Geiser teaches Zip5 knockout mice have increased zinc levels in the liver and decreased zinc levels in the intestine (page 2, ¶5).
Geiser does not teach treating a human subject with decreased serum zinc levels or administering an SLC39A5 inhibitor.
Wang1 teaches that the zinc transporter Zip5 is also called SLC39A5(page 51434, ¶1). Wang1 teaches Zip5 imports zinc into cells (Figure 4C). Wang1 teaches Zip5 is localized to the basolateral plasma membrane when expressed in MOCK polarized cells (¶ spanning pages 51438-42440; Figure 9). Wang1 teaches that Zip5 also localizes to the basolateral plasma membrane in intestinal enterocytes (page 51441, ¶1). Wang1 teaches Zip5 participates in serosal (i.e., serum) to mucosal transport (page 51441, ¶2). Wang1 teaches zinc can be excreted from the body through the pancreas and intestine (page 51441, ¶3). Wang1 suggests that "high level of Zip5 expression in the pancreas and liver may provide serum zinc to these tissues for later excretion into the gut." (page 51441, ¶3).
Jin teaches treating cells with a lentiviral vector encoding an siRNA targeted to SLC39A5 (i.e., administering an SLC39A5 inhibitor) reduces expression of SLC39A5 in human cells (page 1432, ¶7; Figure 2).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used the siRNA targeted to SLC39A5 taught in Jin instead of knocking out SLC39A5 as taught in Geiser for the purpose of treating a zinc serum deficiency in a human subject. It would have amounted to a simple combination of known elements by known means to yield predictable results. Both Geiser and Wang1 teach that SLC39A5/Zip5 is involved in the serum to intestinal transport of zinc for secretion from the body. Thus, one skilled in the art would have predicted that if Zip5 were inhibited in a human subject, 1) the serum to intestinal secretion would decrease, 2) excretion from the body would decrease, and 3) concomitantly serum levels of zinc would increase. Because it is not as feasible to create a gene knockout in human subjects, one skilled in the art would have been motivated to use siRNA to inhibit expression of SLC39A5. One would have predicted that siRNA SLC39A5 would decrease SLC39A5 when administered to human subjects because Jin demonstrates knockdown in human cultured cells.
Regarding claims 15-16, Geiser also teaches administering zinc in the drinking water of the control and knockout mice (Figure 2, ZnE).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have administered zinc as taught in Geiser to a subject with a serum zinc deficiency. Geiser demonstrates the feasibility of providing zinc in drinking water.
Regarding claims 27-29, the teachings of Geiser, Wang1 and Jin, and the obviousness of using an SCL39A5 siRNA and optionally with zinc supplementation, to treat a human subject with decreased serum zinc levels is recited above for claims 1 and 15-16. Geiser and Wang1 both teach determining the functional state of SLC39A5 when comparing wildtype to SLC39A5 knockout status. Jin teaches determining the protein expression level of SLC39A5 (Fig 1F), indicating that the cells are at least wild type (i.e., reference) or heterozygous for a loss-of-function allele.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1, 15-16, 23, 27-29, 36 and 86-93 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 12083141.
Patented claim 1 recites A method of treating a female human subject having an increased serum glucose level and/or hyperglycemia, wherein the subject is Solute Carrier Family 39 Member 5 (SLC39A5) reference or heterozygous for an SLC39A5 predicted loss-of-function variant, the method comprising administering an SLC39A5 inhibitor and a therapeutic agent that treats or inhibits increased serum glucose level and/or hyperglycemia to the subject; wherein the SLC39A5 inhibitor comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA) that hybridizes to an SLC39A5 mRNA; and wherein the therapeutic agent comprises an estrogen, insulin, a sulfonylurea-based agent, a biguanide, or a GLP-1 agonist. Patented claim 2 recites wherein the subject is further administered zinc. Patented claim 4 recites wherein the biguanide comprises metformin, phenformin, and/or buformin. Patented claim 5 recites wherein the GLP-1 agonist comprises liraglutide, exenatide, lixisenatide, albiglutide, dulaglutide, and/or semaglutide. Patented claims 6-7 recite further comprising detecting the presence or absence of an SLC39A5 predicted loss-of-function variant nucleic acid molecule encoding a human SLC39A5 polypeptide in a biological sample from the subject, including SLC39A5 M304T, SLC39A5 G413A, SLC39A5 Y47Stop, SLC39A5 R322Stop, or R311Stop variants. Patented claim 8 recites the method of claim 1 and also including the steps of determining whether the subject has a Solute Carrier Family 39 Member 5 (SLC39A5) predicted loss-of-function variant nucleic acid molecule encoding a human SLC39A5 polypeptide by: obtaining or having obtained a biological sample from the subject; and performing or having performed a genotyping assay on the biological sample to determine if the subject has a genotype comprising the SLC39A5 predicted loss-of-function variant nucleic acid molecule. Therefore, the patented claims anticipate examined claims.
Conclusion
No claims are allowable.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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