DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This Office action is in response to the communication filed 11-22-24.
Claims 1, 3-5, 13-26 are pending in the instant application.
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.
Claims 1, 3-5, 13-26 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 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The breadth of the claims
The claims are drawn to an aqueous formulation comprising particles formed by a combination of polyinosinic-polycytidylic acid [Poly(I:C)] molecules and polyethyleneimine, optionally wherein at least 40% of the Poly(I:C) molecules have at least 850 base pairs, and at least 50% of Poly(1:C) molecules have between 400 and 5000 base pairs; the polyethyleneimine is at least 95% linear polyethyleneimine, has an average molecular weight between 17 and 23 kDa, with a polydispersity index lower than 1.5; and the particles are formed at a ratio of the number of moles of nitrogen of linear- polyethyleneimine to the number of moles of phosphorus of Poly(I:C) molecules that is equal to or greater than 2.5, and optionally the particles have a mono-modal diameter distribution with at least 95%or 99% of the particle having a diameter of less than or equal to 400 nm, a z-average diameter of less than or equal to 250 nm, and a polydispersity index of the particle diameter that is less than 1.5 and a median diameter (D50%) of between 75 nm and 150 nm.
The teachings in the specification are not representative of the large genus of modulators claimed.
Teachings in the specification
The specification teaches the following:
[00090] The particles in the BO-112 composition have a general tendency to interact electrostatically and/or to form aggregates due to attraction/repulsion forces existing between PEI and Poly(I:C) molecules, i.e., the components of particles comprised in the suspension. A small fraction of such particles is in the near-visual (80-100 microns) and visual (100-250 μm) range and can be filtered with a 0.45 μm filter prior to administration. The removal of visual and near-visual range particles by filtration does not cause any change in the potency of the BO-112 compositions due to a minimal impact that these particles have on the total formulation, when maintained at low pH values (~ pH 3). However, an increase of the pH in the formulation by adding a basic solution can cause an alteration of the particle dynamics and aggregation, with the consequential undesirable modification of their size within the BO-112 composition prior to administration.
[00091] The in vitro comparative analysis of buffers that are suitable for deacidifying pharmaceutical formulations prior to administration were performed by considering the main biophysical acceptance criteria for the BO-112 composition, as determined with or without filtration (the pore size was 0.22 µm or 0.45 µm) to confirm that the particle size and structure is not compromised by the deacidification process. The amount of Poly(I:C) molecules in the BO-112 composition is established by measuring A260 value and using, as reference for acceptable loss of material after deacidification, a value lower than 10%. The tendency to form aggregates is established by measuring the A400 value using, as a reference for acceptable value after deacidification, a value lower than 0.25. The experiment was performed by using concentrated buffer solutions at high (basic) pH that can be added in a very small volume to the BO-112 composition to avoid dilution. The details of this comparative analysis, indicating the percentage of material that is lost upon filtration (determined according to the A260 value) or tendency to form aggregates (determined according to the A400 value), are shown in Table 2.
[00093] This experiment confirms that a potent deacidifying buffer (e.g., sodium hydroxide) is clearly able to increase the initial pH of BO-112 composition in the direction of more physiological values. However, an undesirable aggregation of particles is observed. To alleviate this effect, the pH of the BO-112SQ composition may be increased to values above pH 5 using sodium hydroxide with a significantly decreased loss of the Poly(I:C) molecules. However, the resulting A400 value was 0.34, suggesting that the particle size in the BO-112SQ composition in which sodium hydroxide is added is not acceptable for clinical studies. Thus, other deacidifying buffer solutions should be tested to evaluate how a BO-112 composition for specific clinical needs can be obtained with the required features with respect to pH and particle size.
[00094] Three buffer solutions (citrate-phosphate, dipotassium phosphate, and sodium phosphate) that are commercially available at different standard concentrations (e.g., 1M, 0.5M, 0.2M, or 0.1M) and frequently used in the clinical settings, showed a less potent deacidifying effect but produced significant effects on the content of the Poly(I:C) molecules and particle aggregation, which are not compatible with an intended medical administration of the BO-112SQ compositions. However, present data shows that sodium bicarbonate raises the pH in a BO-112SQ composition to acceptable physiological values for the intended administration of a BO-112SQ formulation, altering salient biophysical features in a more limited manner. The exemplary BO-112SQ formulation having a volume of 12 ml contains particles in which 7.2 mg Poly(I:C) molecules are complexed with PEI. The formulation can be administered as injectable solution in which the added volume of deacidifying solution (after a 1:300 dilution) is less than 0.4% of the BO-112 composition, and wherein buffer concentration is less than 0.03% (corresponding to less than 0.004M).
[00098] The UV absorbance at 260 nm (A260) and at 400 nm (A400) was measured for control and test samples as described in Example 1 to compare the structural features of the particles in the alternative BO-112SQ formulations with those of the initial BO-112 formulation. The analyses of physicochemical properties were performed immediately after adding NaHCO3 or after incubation at room temperature for 2 hours using a Dynamic Light Scattering (DLS) equipment. Electrophoretic mobility of control BO-112 or BO-112SQ samples (unfiltered, 0.45 μm filtered, or 0.22 μm filtered) was compared with that of free Poly(I:C) molecules (10 μg of each sample plus gel loading purple dye; NEB, Cat. No. B7025S), using TAE buffer (Invitrogen; Cat. No. AM9869), pre-casted agarose gel…, SyBr-Safe dye…, and an electrophoretic system … Filtered BO-112 and BO-112SQ samples were incubated at room temperature for 24 hours. The electrophoretic mobility of the Poly(I:C) molecules was compared by loading a DNA marker… 1kb DNA ladder…, as a control of nucleic acid size. The concentration of the Poly(I:C) molecules in the respective BO-112 or BO-112SQ samples were later visualized and photographed…
[000104] When the A260 and A400 values are measured after 2 hours of incubation at room temperature immediately after NaH2CO3 addition, the tendency for both A260 and the A400 values to increase with increasing volumes of NaHCO3 added to the BO-112 formulation is confirmed. BO-112SQ formulations that are generated using up to 250 μl NaHCO3 still provide acceptable pH values greater than 5 following the 0.22 μm or standard 0.45 μm filtration, as shown in Table 4.
[000110] The results suggest that deacidification with NaHCO3 in the BO-112SQ formulations does not qualitatively modify the core biological activity of the BO-112 composition. The assays and values described in this Example may be used as guidance for evaluating further intermediate volumes of the 1/6M NaHCO3 solution comprised at a volume of between 150 µl and 250 µl (including 170 µl, 180 µl, 190 µl, 200 µl, 210 µl or 220 µl) for a 12 ml BO-112 composition, wherein these volumes correspond to intermediate values relating to the percentage and molarity of NaHCO3 that is tested in this Example. Moreover, alternative buffers approved by regulatory agencies including the Food & Drug Administration (FDA) or the European Medicines Agency (EMA) and containing any suitable buffer (e.g., acetate, citrate, tartrate, histidine, glutamate, phosphate, Tris, glycine, bicarbonate, succinate, sulphate, or nitrate) may be tested according to the methods disclosed herein to identify suitable buffers yielding alternative BO-112SQ formulations that present comparable features with respect to dilution, volume, molarity, A260 and the A400 reference values as determined when adding sodium bicarbonate to a BO-112 composition.
[000117] …When a BO-11XSQ formulation (or any BO-11X formulation in general) is administered to a subject, the clinical status and response to this treatment may require evaluating not only such biomarkers and imaging data, but also the actual presence of the particles comprised in this formulation within a biological sample obtained from a subject after a period of time following administration to the subject. The period of time can be defined as hours, days, or weeks post-administration. At this stage, the Poly(I:C) molecules present in a biological sample from a subject, in particular serum or plasma, may be used as a surrogate marker for the presence of the particles. However, an assay for performing this evaluation must be sufficiently reliable, reproducible, and robust in order to support the associated clinical research and development activities for determining the optimal route, dosage, and/or regimen for administering the BO-11XSQ formulation (or any BO-11X formulation).
[000118] Sparse evidence in the literature underscores the opportunity for establishing and making use of anti-dsRNA antibodies directed to the double-stranded structures within Poly(I:C) molecules…, but without establishing any specific assay for quantifying Poly(I:C) molecules in a biological sample after clinical administration, let alone when Poly(I:C) molecules are administered in complex forming particles as for BO-11XSQ formulation (and BO-11X formulations in general). This modality of administration requires not only identifying the appropriate conditions for disaggregating the particles present in the biological samples, but also for determining low or trace amounts of Poly(I:C) molecules (e.g., below 100 ng/ml, possibly below 50 ng/ml) such that the timeframe during which the particles containing Poly(I:C) molecules are present and/or if administering higher doses of a BO-11XSQ or BO-11X formulation actually increase the presence of such particles in tissues, blood, or specific fractions (such as plasma) can be determined.
[000120] The data generated using different concentrations of BO-111 (and thus of Poly(I:C) molecules) are then used to establish a calibration profile using analytical software and instruments within a relevant range of Poly(I:C) concentrations. This approach allows for establishing a calibration curve showing a strict linearity between 2.66 ng/ml (LLOQ; signal-to-noise 4:1) and 10.14 ng/mL (ULOQ). This ELISA assay is then tested using aliquots of GMP-manufactured BO-112 compositions, thereby confirming the reliability of the instant approach for quantifying dsRNA in Poly(I:C) molecules as a surrogate measure of Poly(I:C)-containing particles in a liquid sample.
[Citations omitted][Emphases added].
The specification fails to provide the requisite guidance for making and using the large genus of formulations instantly claimed. Since the disclosure fails to describe the common attributes and characteristics concisely identifying members of the proposed genus of formulations, and because the claimed genus is highly variant, the description provided is insufficient, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the broad genus of therapeutic formulations instantly claimed.
Thus, Applicant was not in possession of the broadly claimed genus.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 5, 20-22 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Levitski et al (WO 2010/073247).
Levitski et al (WO 2010/073247) teach compositions comprising polyinosinic polycytidylic ((poly)I:C) molecules and polyethyleneimine (PEI) comprising between pH 5.0 and 7.5, which PEI optionally comprises a linear PEI comprising an average molecular weight of between 17 and 23 kDa (see esp. pages 2-10). Levitsky teach pharmaceutical compositions for intravenous, systemic and intraperitoneal administration (pages 23-28).
The PEI may be branched or linear and has a molecular weight of 1-25 kDa (page 8). Levitski teaches that intratumoral or peritumoral administration of non-targeted polyIC is an effective in antitumor immunotherapy approach, but is limited to localized tumors. Here EGFR targeted (poly)I:C is efficient in the treatment of disseminated tumors that are impossible to treat by local therapy (page 10). Substitution of the branched PEI with linear PEI afforded higher efficiency in killing cancer cells. In the second generation vectors there is only one EGF molecule on each linear PEI molecule vs several EGFs on the branched PEI of the first generation vectors (page 9). Fig. 6 shows the novel second generation vector of pIC/P221PE to have stronger effects on cells with high expression of EGFR and significantly stronger effects on cells with lower expression of EGFR than the first generation vector pIC/MPPE (page 28).
Claim(s) 1, 5, 20-22 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lin et al (J. Biomedical Materials Research Part B, Applied Biomaterials, Vol 107B, No. 4, Part B, pages 1228-1237 (2018))
Lin et al (J. Biomedical Materials Research Part B, Applied Biomaterials, Vol 107B, No. 4, Part B, pages 1228-1237 (2018)) teach compositions comprising polyinosinic polycytidylic molecules and polyethyleneimine (PEI) comprising between pH 5.0 and 7.5, which PEI optionally comprises a linear PEI (see esp. the Abstract on page 1228, text on page 1230, third full paragraph on page 1231, Table 1 on page 1231).
Claim(s) 1, 5, 20-22 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wu et al (Cancer Immunol. Immunother., Vol. 60, pages 1085-1096 (2011)).
Wu et al (Cancer Immunol. Immunother., Vol. 60, pages 1085-1096 (2011)) teach compositions comprising polyinosinic polycytidylic molecules and polyethyleneimine comprising between pH 5.0 and 7.5, which PEI optionally comprises a linier PEI (see esp. the Abstract on page 1085, text on pages 1087-1088, Figure 1 on page 1089, Figure 3 on page 1091).
Claims for products defined in terms of a process of manufacture are allowable only if the products as such fulfil the requirements for patentability, i.e. inter alia that they are new and inventive, and it is impossible to define the claimed product other than in terms of a process of manufacture.
A product is not rendered novel merely by the fact that it is produced by means of a new process. The claim may for instance take the form "Product X obtainable by process Y". Irrespective of whether the term "obtainable", "obtained", "directly obtained" or an equivalent wording is used in the product-by-process claim, it is still directed to the product per se and confers absolute protection upon the product.
As regards novelty, when a product is defined by its method of manufacture, the question to be answered is whether the product under consideration is identical to known products. The burden of proof for an allegedly distinguishing "product-by-process" feature lies with the applicant, who has to provide evidence that the modification of the process parameters results in another product, for example by showing that distinct differences exist in the properties of the products. Nevertheless, the division needs to furnish reasoned argumentation to support the alleged lack of novelty of a product-by-process claim, especially if this objection is contested by the applicant.
See, e.g., the en banc holding Abbott v. Sandoz, 566 F.3d 1282 (Fed. Cir. 2009) following Atlantic Thermoplastics Co. v. Faytex Corp., 970 F.2d 834 (Fed. Cir. 1992), which held that process terms are only considered limitations when the issue is infringement, not patentability. Unlike other claim types, product-by-process claims are in fact treated differently for validity and infringement analyses:
In determining validity of a product-by-process claim, the focus is on the product and not on the process of making it. …. That is because of the already described, long-standing rule that an old product is not patentable even if it is made by a new process. As a result, a product-by-process claim can be anticipated by a prior art product that does not adhere to the claim’s process limitation. In determining infringement of a product-by-process claim, however, the focus is on the process of making the product as much as it is on the product itself. … In other words, “process terms in product-by-process claims serve as limitations in determining infringement.” ... As a result, a product-by-process claim is not infringed by a product made by a process other than the one recited in the claim.
Conclusion
Certain papers related to this application may be submitted to Art Unit 1637 by facsimile transmission. The faxing of such papers must conform with the notices published in the Official Gazette, 1156 OG 61 (November 16, 1993) and 1157 OG 94 (December 28, 1993) (see 37 C.F.R. ' 1.6(d)). The official fax telephone number for the Group is 571-273-8300. NOTE: If Applicant does submit a paper by fax, the original signed copy should be retained by applicant or applicant's representative. NO DUPLICATE COPIES SHOULD BE SUBMITTED so as to avoid the processing of duplicate papers in the Office.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jane Zara whose telephone number is (571) 272-0765. The examiner’s office hours are generally Monday-Friday, 10:30am - 7pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jennifer Dunston, can be reached on (571)-272-2916. Any inquiry of a general nature or relating to the status of this application should be directed to the Group receptionist whose telephone number is (703) 308-0196.
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Jane Zara
2-2-26
/JANE J ZARA/Primary Examiner, Art Unit 1637