DETAILED ACTION
CONTINUED EXAMINATION UNDER 37 CFR 1.114 AFTER FINAL REJECTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant’s submission of RCE and the amendment filed on filed on October 24, 2025 have been entered. The claims pending in this application are claims 1, 5, and 8-11 wherein claim 8 has been withdrawn due to the restriction requirement mailed on February 15, 2024. Claims 1, 5, and 9-11 will be examined.
Claim Rejections - 35 USC § 112
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.
Scope of Enablement
Note that this rejection is modified from the rejection under 35 U.S.C. 112(a) mailed on August 26, 2025.
Claims 1, 5, and 9-11 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 treating ventricular tachycardia of mice having a sickle cell disease and a IL-18 genotype comprising C/T at rs5744285 by intraperitoneal (IP) injecting Interleukin-18-binding protein (IL18 bp) to the mice, does not reasonably provide enablement for treating a human diagnosed with sickle cell disease and ventricular tachycardia by administering Interleukin-18-binding protein (IL18 bp) to any kind of subject diagnosed with sickle cell disease and ventricular tachycardia wherein said IL-18BP is administered via any kind of injection as recited in claims 1, 5, and 9-11. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The Nature of The Invention
The claims are drawn to a method of treating ventricular tachycardia in a human with sickle cell disease. The invention is a class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001).
The Breadth of The Claims
Claims 1, 5, and 9-11 encompass a method of treating ventricular tachycardia in a human with sickle cell disease, comprising: administering interleukin 18 binding protein (IL18BP) to any kind of subject diagnosed with sickle cell disease and the ventricular tachycardia wherein said IL-18BP is administered via any kind of injection.
Working Examples
Although the specification provides 5 working examples (see pages 15-24 of US 2021/0222233 A1, which is US publication of this instant case), the specification provides no working example for treating a human diagnosed with sickle cell disease and ventricular tachycardia by administering Interleukin-18-binding protein (IL18 bp) to any kind of subject diagnosed with sickle cell disease and ventricular tachycardia wherein said IL-18BP is administered via any kind of injection as recited in claims 1, 5, and 9-11.
The Amount of Direction or Guidance Provided and The State of The Prior Art
The specification provides 5 working examples (see pages 15-24 of US 2021/0222233 A1, which is US publication of this instant case). However, the specification provides no working example for treating a human diagnosed with sickle cell disease and ventricular tachycardia by administering Interleukin-18-binding protein (IL18 bp) to any kind of subject diagnosed with sickle cell disease and ventricular tachycardia wherein said IL-18BP is administered via any kind of injection as recited in claims 1, 5, and 9-11.Furthermore, there is no experimental condition and/or experimental data in the specification to support the claimed invention. During the process of the prior art search, the examiner has not found any prior art which is related to treat a human diagnosed with sickle cell disease and ventricular tachycardia by administering Interleukin-18-binding protein (IL18 bp) to any kind of subject diagnosed with sickle cell disease and ventricular tachycardia wherein said IL-18BP is administered via any kind of injection as recited in claims 1, 5, and 9-11.
Level of Skill in The Art, The Unpredictability of The Art, and The Quantity of Experimentation Necessary
While the relative skill in the art is very high (the Ph.D. degree with laboratory experience), there is no predictability whether a human diagnosed with sickle cell disease and ventricular tachycardia can be treated by administering Interleukin-18-binding protein (IL18 bp) to any kind of subject diagnosed with sickle cell disease and ventricular tachycardia wherein said IL-18BP is administered via any kind of injection as recited in claims 1, 5, and 9-11.
First, although the specification teaches that “[T]herapeutic effect of IL-18 blockade by IL-18 bp: The role of IL-18R is investigated by inhibiting IL-18R signaling using IL-18 bp (15 μg/mouse/day) in mice 30 min [based on published kinetics/efficiency of IL-18 bp for IL-18 (Kim et al., 2000. Proc Natl Acad Sci US A 97:1190-1195) prior to isolation of primary cardiomyocytes and intact hearts. The dose and route of IL-18 bp are based on data showing reduced cardiac IL-18R expression with inhibition of IL-18 signaling systemically. Patch clamping is then repeated using the whole-cell configuration as above (n=5) and ex vivo intact heart optical mapping (n=5) with and without IL-18 exposure in the perfusate (2-50 ng/min). Alternatively, siRNA targeting IL-18R systemically (prior to heart harvesting) is utilized”, “[T]he role of IL-18R/Nox4 signaling in the development of cardiac apoptosis and fibrosis in sickle mice. It was previously shown that sustained (3 weeks) IL-18 inhibition using IL-18 bp, which prevents binding of IL-18 to IL-18R, results in reduced myocardial apoptosis and fibrosis associated with reduced cardiac Nox4 and IL-18R expression levels. It is hypothesized that sustained reduced cardiac Nox4 expression leads to decreased rates of myocardial apoptosis and fibrosis in sickle mice. Cardiac-specific Nox4 (cNox4−/−) knockout mice (Kuroda et al., 2010. Proc Natl Acad Sci USA 107:15565-15570) are breed to generate a combination of cardiac Nox4 knockout mice in both a sickle and a sickle control ‘WT’) background. The combined mutant mice may display a vulnerable phenotype upon stressful stimuli. However, at baseline, cNox4−/− mice do not appear to have any obvious cardiovascular or systemic phenotype (Kuroda et al., 2010, supra) nox4 reduction may be beneficial for sickle mice. Alternative approaches including the use of 1) non-specific Nox inhibitors (FIG. 9C), 2) daily systemic siRNA in vivo, or P38 inhibitor (daily IP injections). Levels of myocardial apoptosis and fibrosis, and cardiac function are evaluated using echocardiography in these animals at 10-14 weeks and ‘WT”, “WT’-cNox4−/−, sickle, and sickle-cNox4−/− mice are compared at baseline. IL-18 bp is then administered (1 μg/kg IP every other day for three weeks) and harvest mice as well as perform echo as described above. As separate experiments, IL-18 injections (25 μg/kg, IP based Yu et al., 2009. Am J Physiol Heart Circ Physiol 297:H76-85)] are administered daily for three weeks to these same strains of mice to determine levels of myocardial apoptosis, fibrosis, and function. These latter experiments provide information on the contribution of cardiac Nox4-specificty to IL-18 signaling in sickle cardiomyopathy including the potential for nox4 independent-influences. Ten replicates per strain (males, 10-14 weeks of age for phenotyping/harvesting tissue) are performed for all of the chronic experiments. A subset of these bred mice are subject to patch clamping and optical mapping. In some embodiments, antibodies are acquired from commercial sources and validated using several criteria: single band of the expected molecular weight by Western blot, use of positive and negative control cell lines and tissue sources (knockdown using siRNA or knockout murine tissues when available) and reproducibility between experimental runs and antibody lots”, “[D]rugs that will either reduce circulating heme/hemolysis or IL-18 activity (directly or indirectly) that is specific to sickle cell disease are investigated. In particular, the effects of IL-18 antibody (IL-18ab) and the arrhythmic phenotype in a combined genetically-depleted cardiac Nox4−/−/sickle transgenic mouse is tested. Hydroxyurea is tested for its ability to reduced hemolysis and improved mortality in sickle patients. Since hydroxyurea responses are variable (one third of patients do not respond), decitabine, an FDA-approved drug for myeloproliferative disorders which shows significant promise in reducing hemolysis and inducing Hemoglobin F in sickle cell patients, including those who do not respond to hydroxyurea is also tested”, “[B]ased on data (below) in sickle mice modeling a human electrophysiology (EP) study, the experimental model provides an excellent platform to screen for mechanisms and drug therapies in the arrhythmic-vulnerable sickle myocardium. While pacing-induced VT during an EP study in parallel conditions such as hypertrophic cardiomyopathy has shown mixed predictive and prognostic value (Behr et al., 2002. Card Electrophysiol Rev 6:482-486), the current observation in sickle cell mice may, nonetheless, still hold significant implications for an EP study on the vulnerability of sickle cardiomyopathy to spontaneous or inducible VT. Specifically, murine (and human) sickle cardiomyopathy is characterized by three conventional VT risk factors including fibrosis, diastolic dysfunction, and prolonged APD (Al-Zaiti et al., 2014. Heart Lung 43:527-533; Kenigsberg et al., 2007. J Am Coll Cardiol 49:1299-1305; Remme and Wilde, 2013. Cardiovasc Drugs Ther 27:91-101; Sara et al., 2016. J Electrocardiol 49:87-93; Schwartz and Wolf, 1978. Circulation 57:1074-1077) which contribute to its pathological electrophysiology remodeling, resembling the concept of ‘reduced repolarization reserve’ (Roden, 1998. Pacing Clin Electrophysiol 21:1029-1034). This concept has been previously proposed as a general condition that promotes long QT-related arrhythmias such as EADs and Torsades de Pointes in particular with further stress. Both IL-18 administration or an EP study are therefore examples of these stressors and tools that can induce VT and validate this concept in sickle cell mice”, “[T]he same in vivo protocol used in (Rutledge et al., 2014. J Am Coll Cardiol 63:928-934) and the data below are used. Mice are anesthetized and intubated, before initiating an open-chest catheter protocol. Baseline ECG are acquired for 2 minutes (Millar); the data is stored and analyzed offline using the LabChart 7.1 (AD Instrument) software. Lead II recordings will be chosen for analyses. Programmed ventricular stimulation will be performed with a RV epicardial electrode connected to STG1008 stimulator (Multichannel systems, Reutlingen, Germany), where eight consecutive beats will be paced at 60 ms basic cycle length, followed by single, double and triple extra stimuli with incrementally deceasing cycle lengths between 20-55 ms, and inducible ventricular tachycardia will be defined as >3 consecutive ventricular beats. All experiments will be done with n=10 replicates for reproducibility and to meet power calculations”, “[S]ickle mice are vulnerable to pacing-induced VT. Sickle homozygous and sickle control (‘WT’) underwent an open-chest EP study (while intubated and anesthetized) in vivo where hearts of mice were stimulated with a catheter to induce rapid pacing (via either a programmatic or burst protocol). Unlike WT mice, nearly all but two sickle mice exhibited polymorphic VT (FIG. 12)”, [E]valuation of VT vulnerability in vivo in sickle mice after treatment with IL-18ab and with genetic depletion of cNox4−/− (combination mutant mouse). There are also early clinical trials of injectable IL-18 blocking antibodies (O'Brien et al., 2014. Mol Med 20:221-229) in type 2 diabetes. The primary advantage of an IL-18 neutralizing /blocking antibody (IL-18ab) is a longer elimination half-life that may allow monthly or quarterly administration. The efficacy of IL-18ab (5 mg/kg ip daily for three weeks vs vehicle, n=10 per strain, males, 10-14 weeks of age) is tested in the established inducible VT model in 3 mice strains (sickle control or ‘WT’, heterozygote, homozygous). Heart tissue is evaluated for IL-18R Nox4, p38 activation levels, and fibrosis/apoptosis. Four more strains (‘WT’, combination of cNox4−/− in a ‘WT’, sickle, combination of cNox4−/− in a sickle mouse) are assessed to determine VT vulnerability under Nox4 depletion (n=10 per strain, males, 10-14 weeks of age)”, “[H]ydroxyurea (n=10 per strain per dosing regimen, males, 10-14 weeks of age) is administered in two dosing schedules: 1) gavage with hydroxyurea or its vehicle (250 mg/kg orally as a one-time dose and prepared fresh, Sigma) 10 hours prior to EP testing 2) daily injection (50 mg/kg, IP) 5 days a week for 4 weeks prior to EP testing. The first dose tests whether there are any immediate beneficial effects that are brought about by stressing the heart with an EP study acutely. The second dose determines whether long-term hydroxyurea use may be able to prevent inducible VT in sickle mice despite the absence of change in heme levels (and in hemoglobin F/hemoglobin) via other yet unknown mechanisms including any effects on myocardial remodeling (e.g., fibrosis). Heart tissue is evaluated for levels of myocardial IL-18R Nox4, p38 activation, and myocardial fibrosis/ apoptosis. A subset of these mice that are receiving hydroxyurea are administered IL-18 ex vivo to determine whether hydroxyurea will prevent IL-18 induced prolonged APD and VT (Lebensburger et al., 2010. Haematologica 95: 1599-1603; Almeida et al., 2012. Blood, 120:2879-2888)”, and “[A] subset of these mice that are receiving decitabine are administered IL-18 ex vivo to determine whether decatibine will prevent IL-18 induced prolonged APD and VT (Lebensburger et al., 2010. Haematologica 95:1599-1603; Almeida et al., 2012. Blood
120:2879-2888)” (see paragraphs [0195], [0197] to [0202], [0204], and [0206], and Figure 12 of US 2021/0222233 A1, which is US publication of this instant case) and applicant’s paper shows that “[W]e hypothesize that interleukin-18 (IL-18) mediates the development of cardiomyopathy and ventricular tachycardia (VT) in SCD. Compared with control mice, a humanized mouse model of SCD exhibited increased cardiac fibrosis, prolonged duration of action potential, higher VT inducibility in vivo, higher cardiac NF-kB phosphorylation, and higher circulating IL-18 levels, as well as reduced voltage-gated potassium channel expression, which translates to reduced transient outward potassium current (Ito) in isolated cardiomyocytes. Administering IL-18 to isolated mouse hearts resulted in VT originating from the right ventricle and further reduced Ito in SCD mouse cardiomyocytes. Sustained IL-18 inhibition via IL-18-binding protein resulted in decreased cardiac fibrosis and NF-kB phosphorylation, improved diastolic function, normalized electrical remodeling, and attenuated IL-18-mediated VT in SCD mice. Patients with SCD and either myocardial fibrosis or increased QTc displayed greater IL18 gene expression in peripheral blood mononuclear cells (PBMCs), and QTc was strongly correlated with plasma IL-18 levels. PBMC-derived IL18 gene expression was increased in patients who did not survive compared with those who did. IL-18 is a mediator of sickle cell cardiomyopathy and VT in mice and a novel therapeutic target in patients at risk for sudden death” (see abstract from Gupta et al., Blood, 137, 1208-1218, 2021), the scope of claim 1 is much broader than the scope of the teachings of the specification since the specification only teaches treating ventricular tachycardia of mice having a sickle cell disease and a IL-18 genotype comprising C/T at rs5744285 by intraperitoneal (IP) injecting Interleukin-18-binding protein (IL18bp) to the mice and does not provide any data for treating a human diagnosed with sickle cell disease and ventricular tachycardia by administering Interleukin-18-binding protein (IL18 bp) to any kind of subject diagnosed with sickle cell disease and ventricular tachycardia wherein said IL-18BP is administered via any kind of injection method as recited in claims 1, 5, and 9-11. Since the content of claim 1 does not require that a subject diagnosed with sickle cell disease and ventricular tachycardia is a human diagnosed with sickle cell disease and ventricular tachycardia, if the subject diagnosed with sickle cell disease and ventricular tachycardia is the human diagnosed with sickle cell disease and ventricular tachycardia, it is unpredictable how data for treating any kind of subject diagnosed with sickle cell disease and ventricular tachycardia can be used for treating a human diagnosed with sickle cell disease and ventricular tachycardia. Furthermore, although the specification and applicant’s paper teach that ventricular tachycardia of mice having a sickle cell disease and a IL-18 genotype comprising C/T at rs5744285 can be treated by intraperitoneal (IP) injecting Interleukin-18-binding protein (IL18bp) to the mice, since the specification and applicant’s paper do not teach that any kind of subject diagnosed with sickle cell disease and ventricular tachycardia and having a IL-18 genotype comprising C/T at rs5744285 can be treated with Interleukin-18-binding protein (IL18bp), and claim 1 does not require that said subject has a IL-18 genotype comprising C/T at rs5744285, if said subject does not have a IL-18 genotype comprising C/T at rs5744285, it is unpredictable how any kind of subject diagnosed with sickle cell disease and ventricular tachycardia can be treated by administering Interleukin-18-binding protein (IL18 bp) to any kind of subject diagnosed with sickle cell disease and ventricular tachycardia wherein said IL-18BP is administered via any kind of injection as recited in claims 1, 5, and 9-11.
Second, since Interleukin-18-binding protein (IL-18 bp) recited in claim 1 is a protein, the injection of the administering step of claim 1 is read on protein delivery via various injection routes in vivo. The injection route includes subcutaneous, intravenous, intramuscular, intrathecal, intraperitoneal, and intranasal injection etc. It is known that protein delivery into cells in vivo is very challenging. Mechanical/physical methods such as microinjection and electroporation are the most traditional methods for protein delivery in vitro. In vivo use of these methods is complicated by the need for direct physical access to the targeted cells, which limits the volume of tissue that can be locally treated. Additionally, the transient cell permeabilization provided by these approaches allows influx of other proteins and biomolecules into the cell, generating potential side effects and in vivo delivery features substantial additional challenges beyond cellular uptake, including biodistribution, pharmacokinetics, and immune response (see pages 1602 and 1603 from Fu et al., Bioconjugate Chemistry, 25, 1602-1608, 2014). The art of delivering a protein or peptide to various target sites in vivo was unpredictable before the effective filing date of the claimed invention. There are various barriers before a protein can reach its target cells, for example, layers of dermal cells, blood vessel wall cell membranes, proteases and lysosomal degradation within cells, extracellular matrix between cells, gastrointestinal digestive acids, and blood-brain barrier for reaching cells in the brain. Whether the protein or peptide can reach target cells in vivo or not depends on the administration route of said protein.
Turner et al., (Journal of Pharmaceutical Sciences, 107, 1247-1260, 2018) discuss challenges and approaches for subcutaneous (SC) administration of therapeutic proteins. Subcutaneous administration of therapeutic proteins is affected by many factors such as sizes and charges of the therapeutic proteins, FcRn binding affinity of the therapeutic proteins, injection volume and site of injection of the therapeutic proteins, injected concentration of the therapeutic proteins, buffer conditions of the therapeutic proteins, and formulation excipients and additive and they indicated that “caution must be applied when using animal models for predictive purposes and scale-up approaches, as biotherapeutic absorption varies wildly species to species” (see page 1257, left column, second paragraph).
Zou et al., (Journal of Controlled Release, 336, 310-321, 2021) discuss impact of injection sites on clinical pharmacokinetics of subcutaneously administered peptides and proteins. They indicated that “SC absorption of proteins and peptides is a complex process. In addition to the factors investigated in this study, many other intrinsic factors (i.e. body mass index, gender, age) and extrinsic factors (i.e. exercise, injection device) may potentially affect SC absorption from different injection sites. Further investigations are needed to understand underlying mechanisms of injection site-dependent SC absorption” (see page 319, right column, second paragraph).
It is apparent that there are numerous barriers for protein delivery to target cells in vivo and those barriers include high enzymatic susceptibility, short shelf life, intestinal epithelial barrier, capillary endothelial barrier, poor permeability characteristics throughout various mucosal surfaces and biological membranes, poor absorption, hepatic metabolism, and immune response from the host. Since the claims do not indicate how Interleukin-18-binding protein (IL18 bp) is administered to the subject with sickle cell disease and ventricular arrhythmia, it is unpredictable how any kind of subject diagnosed with sickle cell disease and any kind of ventricular arrhythmia can be treated by administering Interleukin-18-binding protein (IL18 bp) to the subject using any kind of administering method as recited in claims 1, 5, and 9-11.
Case law has established that “(t)o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation’.” In re Wright 990 F.2d 1557, 1561. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) it was determined that “[T]he scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art”. The amount of guidance needed to enable the invention is related to the amount of knowledge in the art as well as the predictability in the art. Furthermore, the Court in Genentech Inc. v Novo Nordisk 42 USPQ2d 1001 held that “[I]t is the specification, not the knowledge of one skilled in the art that must supply the novel aspects of the invention in order to constitute adequate enablement”.
In view of above discussions, the skilled artisan will have no way to predict the experimental results. Accordingly, it is concluded that undue experimentation is required to make the invention as it is claimed. The undue experimentation at least includes to test whether any kind of subject diagnosed with sickle cell disease and any kind of ventricular arrhythmia can be treated by administering Interleukin-18-binding protein (IL-18 bp) to the subject using any kind of administering method as recited in claims 1, 5, and 9-11.
Conclusion
In the instant case, as discussed above, the level of unpredictability in the art is high, the specification provides one with no guidance that leads one to claimed methods. One of skill in the art cannot readily anticipate the effect of a change within the subject matter to which the claimed invention pertains. Thus given the broad claims in an art whose nature is identified as unpredictable, the unpredictability of that art, the large quantity of research required to define these unpredictable variables, the lack of guidance provided in the specification, the absence of any working example related to claimed invention and the no teaching in the prior art balanced only against the high skill level in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the method of the claim as broadly written.
Response to Arguments
In page 4, third paragraph bridging to page 6, third paragraph of applicant’ remarks, applicant argues that “[A]pplicant submits that the Examiner has provided no evidence that the model animal used in the experimental section of the presently claimed invention does not correlate with use of the method on human subjects. In addition, the specification provides data on the effect of IL-18BP on sickle cell mice (See e.g., FIG. 2A, pg. 51, lines 13-2) regardless of IL-18 genotype. Thus, applicant submits that the claims are enabled for treatment of all subjects with sickle cell disease”, “[T]he specification (See e.g., Examples 1-5) clearly provides a role for IL-18 in ventricular tachycardia. In particular, Examples 1 and 4 and FIG. 2A describe the use of IL-18BP in treating ventricular tachycardia. Further, the Examiner has acknowledged that the claims are enabled for treating ventricular tachycardia”, and “[A]pplicant submits that one of ordinary skill in the art would be able to administer IL-18BP using any injection method, not just using IP injection. The specification describes multiple methods for administering IL-18BP (See e.g., pg. 34, line 27 to page 35, line 34). In addition, at the time of filing, methods of administering IL-18BP by injection were known in the art (See e.g., Tak et al and Ouzounidis et al; each of which is attached hereto). These publications demonstrate the IL-18BP can be administered via injection (e.g., IV or SC injection) and be active. Thus, applicant submits that the claims are enabled for administration by injection. Applicant submits that one of ordinary skill in the art, reading the present specification, would not need to perform undue experimentation to practice the presently claimed invention.The claims are directed to treating a specific disease in a specific population with a specific class agent that is described in detail in the specification”.
These arguments have been fully considered but they are not persuasive toward the withdrawal of the rejection.
First, since the content of claim 1 does not require that a subject diagnosed with sickle cell disease and ventricular tachycardia is a human diagnosed with sickle cell disease and ventricular tachycardia, if the subject diagnosed with sickle cell disease and ventricular tachycardia is the human diagnosed with sickle cell disease and ventricular tachycardia, it is unpredictable how data for treating any kind of subject diagnosed with sickle cell disease and ventricular tachycardia can be used for treating a human diagnosed with sickle cell disease and ventricular tachycardia. Furthermore, although the specification and applicant’s paper teach that ventricular tachycardia of mice having a sickle cell disease and a IL-18 genotype comprising C/T at rs5744285 can be treated by intraperitoneal (IP) injecting Interleukin-18-binding protein (IL18bp) to the mice, since the specification and applicant’s paper do not teach that any kind of subject diagnosed with sickle cell disease and ventricular tachycardia and having a IL-18 genotype comprising C/T at rs5744285 can be treated with Interleukin-18-binding protein (IL18bp), and claim 1 does not require that said subject has a IL-18 genotype comprising C/T at rs5744285, if said subject does not have a IL-18 genotype comprising C/T at rs5744285, it is unpredictable how any kind of subject diagnosed with sickle cell disease and ventricular tachycardia can be treated by administering Interleukin-18-binding protein (IL18 bp) to any kind of subject diagnosed with sickle cell disease and ventricular tachycardia wherein said IL-18BP is administered via any kind of injection as recited in claims 1, 5, and 9-11.
Second, since Interleukin-18-binding protein (IL-18 bp) recited in claim 1 is a protein, the injection of the administering step of claim 1 is read on protein delivery via various injection routes in vivo. The injection route includes subcutaneous, intravenous, intramuscular, intrathecal, intraperitoneal, and intranasal injection etc. It is known that protein delivery into cells in vivo is very challenging. Mechanical/physical methods such as microinjection and electroporation are the most traditional methods for protein delivery in vitro. In vivo use of these methods is complicated by the need for direct physical access to the targeted cells, which limits the volume of tissue that can be locally treated. Additionally, the transient cell permeabilization provided by these approaches allows influx of other proteins and biomolecules into the cell, generating potential side effects and in vivo delivery features substantial additional challenges beyond cellular uptake, including biodistribution, pharmacokinetics, and immune response (see pages 1602 and 1603 from Fu et al., Bioconjugate Chemistry, 25, 1602-1608, 2014). The art of delivering a protein or peptide to various target sites in vivo was unpredictable before the effective filing date of the claimed invention. There are various barriers before a protein can reach its target cells, for example, layers of dermal cells, blood vessel wall cell membranes, proteases and lysosomal degradation within cells, extracellular matrix between cells, gastrointestinal digestive acids, and blood-brain barrier for reaching cells in the brain. Whether the protein or peptide can reach target cells in vivo or not depends on the administration route of said protein.
Turner et al., (Journal of Pharmaceutical Sciences, 107, 1247-1260, 2018) discuss challenges and approaches for subcutaneous (SC) administration of therapeutic proteins. Subcutaneous administration of therapeutic proteins is affected by many factors such as sizes and charges of the therapeutic proteins, FcRn binding affinity of the therapeutic proteins, injection volume and site of injection of the therapeutic proteins, injected concentration of the therapeutic proteins, buffer conditions of the therapeutic proteins, and formulation excipients and additive and they indicated that “caution must be applied when using animal models for predictive purposes and scale-up approaches, as biotherapeutic absorption varies wildly species to species” (see page 1257, left column, second paragraph).
Zou et al., (Journal of Controlled Release, 336, 310-321, 2021) discuss impact of injection sites on clinical pharmacokinetics of subcutaneously administered peptides and proteins. They indicated that “SC absorption of proteins and peptides is a complex process. In addition to the factors investigated in this study, many other intrinsic factors (i.e. body mass index, gender, age) and extrinsic factors (i.e. exercise, injection device) may potentially affect SC absorption from different injection sites. Further investigations are needed to understand underlying mechanisms of injection site-dependent SC absorption” (see page 319, right column, second paragraph).
It is apparent that there are numerous barriers for protein delivery to target cells in vivo and those barriers include high enzymatic susceptibility, short shelf life, intestinal epithelial barrier, capillary endothelial barrier, poor permeability characteristics throughout various mucosal surfaces and biological membranes, poor absorption, hepatic metabolism, and immune response from the host. Since the claims do not indicate how Interleukin-18-binding protein (IL18 bp) is administered to the subject with sickle cell disease and ventricular arrhythmia, it is unpredictable how any kind of subject diagnosed with sickle cell disease and any kind of ventricular arrhythmia can be treated by administering Interleukin-18-binding protein (IL18 bp) to the subject using any kind of administering method as recited in claims 1, 5, and 9-11.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 5, and 9-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4-7 of U.S. Patent No. 11,091,795 B2. Although the conflicting claims are not identical, they are not patentably distinct from each other because the examined claims in this instant application are either anticipated by, or would have been obvious over, the reference claims. See 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); and, In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969). Although claims 1, 5, and 9-11 in this instant application are not identical to claims 4-7 of U.S. Patent No. 11,091,795 B2, claims 4-7 of U.S. Patent No. 11,091,795 B2 are directed to the same subject matter and fall entirely within the scope of claims 1, 5, and 9-11 in this instant application. In other words, claims 1, 5, and 9-11 in this instant application are anticipated by claims 4-7 of U.S. Patent No. 11,091,795 B2.
Response to Arguments
In page 6, fourth paragraph of applicant’ remarks, applicant argues that “[A]pplicants respectfully request that the rejection be held in abeyance until all remaining rejections have been overcome”.
This argument has been fully considered but it is not persuasive toward the withdrawal of the rejection because applicant has not filed a terminal disclaimer yet.
Conclusion
No claim is allowed.
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/FRANK W LU/
Primary Examiner, Art Unit 1683
February 9, 2026