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 .
Election/Restrictions
Applicant’s election of Species A (i.e., a single and specific stable formulation as a lyophilized formulation comprising an anti-cancer peptide comprising a fusion of SEQ ID NO: 1 as the HDM-2 binding component and SEQ ID NO: 25 as the membrane resident component in a concentration of 25 mg/ml, acetate buffer in a concentration of 1.36 mg/ml, mannitol in a concentration of 40 mg/ml, sucrose in an amount of 20%, NaCl, polysorbate 20 in an amount of 0.1% at a pH of 5.1, having a particle size of 1.5 nm, and exhibiting the property where less than 1% of the anti-cancer peptide is degraded after 5 years of storage at 2-8°C) in the reply filed on February 12, 2026, is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Please not that although Applicants indicate that mannitol is present in an amount of 40 mg, given that mannitol is in an aqueous solution to be lyophilized, it is being presumed that the concentration is 40 mg/ml. Also please note, the particle size of 1.5 nm would necessarily result in particles not being greater than about 2.0 nm, 3.0 nm, or 5.0 nm as recited in instant claims 17-19.
Status of Claims
Claims 1-24 were originally filed on January 18, 2023.
The amendment received on January 18, 2023, amended claims 3-7, 9-15, and 18-24. The amendment received on February 12, 2026, amended claim 6 and 16.
Claims 1-24 are currently pending and claims 16-19 and 22-24 are under consideration as claims 1-15 and 20-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on February 12, 2026.
Priority
The present application claims status as a 371 (National Stage) of PCT/US2020/067161 filed December 28, 2020, and claims priority under 119(e) to U.S. Provisional Application No. 62/957,531 filed on January 6, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on March 30, 2023, is being considered by the examiner.
Claim Interpretation
For purposes of applying prior art, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation set forth below, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
For claim 16, with respect to the HDM-2 binding component, it is noted that the instant specification does not define what is encompassed by a HDM-2 binding component. As such, the plain and ordinary meaning of the term applies. The claimed component encompasses any structure such as peptides, proteins, saccharides, nucleic acids, small molecules, etc. that bind to HDM-2. Table 1 in the instant specification lists 24 different peptides that bind to HDM-2, i.e., SEQ ID NOs: 1-24 (See instant, Table 1 at pgs. 5-7). The instant specification also teaches that the HDM-2 binding component is an antibody or antibody fragment (See instant, pg. 7, 1st paragraph), or a small molecule with the structure of compounds (I) or (II) (See instant, pg. 8, 2nd paragraph to pg. 10, 2nd paragraph). Two specific species of small molecule structures are depicted on page 11 of in the instant specification. However, since the claimed HDM-2 binding component is a component of a peptide, the HDM-2 binding component is limited to the species listed in Table 1. Although there is no shared core structure or sequence between SEQ ID NOs: 1-24, these 24 sequences constitute a representative number of peptides that bind to HDM-2. Thus, an ordinary skilled artisan would conclude that the applicant was in possession of the claimed genus before the effective filing date of the instant application.
With respect to the membrane resident component, it is noted that the instant specification does not define what is encompassed by a membrane resident component. As such, the plain and ordinary meaning of the term applies. The claimed component encompasses any structure such as peptides, proteins, saccharides, nucleic acids, small molecules, etc. that would interact with a membrane. Table 2 in the instant specification lists 23 different membrane resident peptides (MRPs) that function as membrane resident peptides, i.e., SEQ ID NOs: 25-47 (See instant, Table 2, pgs. 12-14). The instant specification also teaches that the membrane resident component is a small molecule with the structure depicted on pg. 15 (See instant, pg. 15, 1st paragraph to pg. 18, last paragraph). However, since the claimed membrane resident component is a component of a peptide, the membrane residue component is limited to the species listed in Table 2. Although there is no shared core structure or sequence between SEQ ID NOs: 25-47, these 23 sequences constitute a representative number of peptides that function as a membrane resident component. Thus, an ordinary skilled artisan would conclude that the applicant was in possession of the claimed genus before the effective filing date of the instant application.
With respect to the anti-cancer peptide, it is noted that the instant specification does not define what constitutes a peptide that exhibits the function of being anti-cancer. The anti-cancer peptide requires at least two components, i.e., the HDM-2 binding component and the membrane resident component. Although, the specification provides a representative number of species for each of the components of the peptide, the scope of cancers in which the peptide is to treat, i.e., “anti-cancer”, encompasses any cancer without any relationship to the required components. Table 3 lists 4 sequences that are anti-cancer peptides, i.e., SEQ ID NOs: 48-51, where each of the four sequences utilize the same membrane resident component, i.e., SEQ ID NO: 25 (See instant, Table 3 at pgs. 20-21). However, the state of the art demonstrates that SEQ ID NOs: 48-49 exhibit anti-cancer effects against a representative number of cancers. Pincus et al. US 2011/0183915 A1 demonstrates that instant SEQ ID NOs: 48-49 (i.e., PNC-27 and PNC-28, respectively) exhibits an anti-cancer effect on pancreatic cancer, brain angiosarcoma, cervical squamous cell cancer, non-small cell lung cancer, breast cancer, osteosarcoma, ovarian cancer, and melanoma (See Pincus, Figures 4 and 13A-C). Moreover, Wang et al. teaches that HDM2 regulates the activity of the tumor suppressor protein p53 (See Wang et al., Leukemia 34:75-86 (July 2019) at abstract). Wang et al. also teaches that a p53-independent HDM-2 expression has been reported on the membrane of cancer cells but not on that of normal cells (See Wang, abstract). For example, HDM2 has been found to be expressed on the cell membrane of solid tumor cells, e.g., colon, breast and pancreas (See Wang, pg. 75, col. 2, last paragraph). Wang et al. also found that membrane HDM-2 is expressed on human and mouse acute myeloid leukemia (AML) cells where PNC-27 binds to the mHDM-2 resulting in significant killing of the AML cells (See Wang, abstract). Thus, the state of the art demonstrates that the required HDM-2 binding component in the anti-cancer peptide would exhibit anti-cancer effects against a representative number of cancers that express HDM-2. Therefore, an ordinary skilled artisan would conclude that the applicant was in possession of the claimed genus before the effective filing date of the instant application.
Drawings
The drawings; in particular, Figures 1-4, are objected to because of the following reason:
The drawings refer to blue, green, and red, presumably blue, green and red lines in the figure. See 37 CFR 1.84(a)(2); See Figure(s) 1-4.
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities: the last paragraph on pg. 37 refers to Table 1, but it appears it should be Table 4; the last paragraph on pg. 39 refers to Table 2 as describing formulation details and tabulated data for a set of 5 formulations with differing pH values, but Table 2 is on pg. 12-14 listing species of membrane resident peptides; the last paragraph on pg. 41 refers to Table 2, but it appears it should be Table 5; and the last paragraph on pg. 42 refers to Table 3, but it appears it should be Table 6.
Appropriate correction is required.
The disclosure is objected to because of the following informalities: Table 1 on pg. 6 lists HDM-2 binding peptides where SEQ ID NOs: 9 and 11 include X residues. It is respectfully requested that the specification indicate that the X residues correspond to any amino acid as indicated in the Sequence Listing in order to provide clarity. Furthermore, it is respectfully requested that the dashes in SEQ ID NO: 11 are removed given that there are no intervening residues and/or moieties in the sequence as indicated in the Sequence Listing. Appropriate correction is required.
Claim Objections
Claim 16 is objected to because of the following informalities: claim 16 recites, “an HDM-2 binding component…” Although, the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The Examiner respectfully requests that Applicant uses human double minute 2 protein (HDM-2) binding component for the first recitation, thereafter HDM-2 binding component may be utilized. Appropriate correction is required.
Claim 16 is objected to because of the following informalities: claim 16 recites, “the formulation is reconstitutable…” It is respectfully requested that claim 16 recites, “the lyophilized formulation is reconstitutable…” in order to clearly indicate which formulation is being referred to. Appropriate correction is required.
Claim 17 is objected to because of the following informalities: claim 17 recites, “wherein particle-free solution…” It is respectfully requested that claim 17 recites, “wherein the particle-free solution…” in order to be grammatically correct. Appropriate correction is required.
Claims 22-24 are objected to because of the following informalities: claims 22-24 recite, “about 2-8 °C”. It is respectfully requested that claims 22-24 recite, “about 2-8°C” in order to be grammatically correct. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 16-19 and 22-24 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. Claim 16 recites the limitation "the formulation" in 4. It is noted that claim 16 recites a stable, lyophilized formulation in line 1 and an aqueous formulation in line 2. As such, it is unclear which formulation has a pH of about 4.0-6.0. Thus, there is insufficient antecedent basis for this limitation in the claim.
Please note that the Examiner is interpreting the scope of claim 16 such that the lyophilized formulation has a pH of about 4.0-6.0 in order to advance prosecution. Also please note that claims 17-19 and 22-24 are rejected by virtue of their dependency.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 17-19 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 17-19 are directed to where the particle-free solution comprises no particles greater than about 2.0 nm, about 3.0 nm, or about 5.0 nm. However, claims 17-19 are dependent upon claim 16, which requires that the formulation is reconstitutable with a liquid to become a particle-free solution containing about 20-30 mg/ml concentration of the anti-cancer peptide within about 2 minutes or less. It is noted that the instant specification does not define what is meant by a “particle-free” solution. As such, the plain and ordinary meaning of the term applies, i.e., excluding any particles of any size. Since claim 16 does not encompass any particles of any size in the reconstituted solution, the scope of claims 17-19, which encompass a solution with specific particle sizes broaden the scope of claim 16. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Please note that the Examiner is interpreting that claim 19 is incorporated into claim 16 in order to advance prosecution. Moreover, the Examiner suggests for claims 17 and 18 to be switched such that claim 17 is dependent upon claim 18. Such an amendment would render the scope of claims 17-18 as properly further limiting claim 16 as suggested.
Claims 18-19 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 18 is directed to where the particle-free solution comprises no particles greater than about 3.0 nm, and claim 19 is directed to where the particle-free solution comprises no particles greater than about 5.0 nm. However, claim 18 is dependent upon claim 17, and claim 19 is dependent upon claim 18. Claim 17 is directed to where the particle-free solution comprises no particles greater than about 2.0 nm (note: “about” is not defined in the specification, and thus, is being interpreted as +/- 10% thereby correlating to a particle size range of 1.8 to 2.2 nm). As such, the scope of claim 17 already excludes particle sizes greater than about 3.0 nm or greater than about 5.0 nm. Thus, larger particles between 2.2 nm and 5.5 nm are already excluded in claim 17. Similarly, the scope of claim 18 already excludes particle sizes greater than 3.3 nm (i.e., about 3.0 nm). Thus, larger particles between 3.3 nm and 5.5 nm are already excluded in claim 18. In fact, the scope of claim 18-19 broadens the scope of claim 17, and the scope of claim 19 broadens the scope of claim 18 because the each dependent claim encompasses larger particle sizes than the claim upon which it depends. For example, claim 18 encompasses where the particle-free solution comprises particles of 2.5 nm whereas claim 17 does not. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Please note that the Examiner is interpreting that claim 19 is incorporated into claim 16 in order to advance prosecution. Moreover, the Examiner suggests for claims 17 and 18 to be switched such that claim 17 is dependent upon claim 18. Such an amendment would render the scope of claims 17-18 as properly further limiting claim 16 as suggested.
Claims 23-24 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 23 is directed to where less than about 1% of the anti-cancer peptide is degraded after about 3 years of storage at about 2-8°C, and claim 24 is directed to where less than about 1% of the anti-cancer peptide is degraded after about 5 years of storage at about 2-8°C. However, claim 23 is dependent upon claim 22, and claim 24 is dependent upon claim 23. Claim 22 is directed to where less than about 1% of the anti-cancer peptide is degraded after about 2 years of storage at about 2-8°C (note: “about” is not defined in the specification, and thus, is being interpreted as +/- 10% thereby correlating to a storage duration of 21.6 months to 26.4 months). As such, the storage duration range encompassed by claim 22 does not encompass the storage duration ranges recited in claims 23-24, i.e., 32.4 months to 39.6 months and 44 months to 66 months, respectively. Thus, the scope of claims 23-24 do not further limit the scope of claim 22, and the scope of claim 24 does not further limit the scope of claim 23. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 16-19 and 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Pincus et al. US Publication No. 2011/0183915 A1 published on July 28, 2011 in view of Schultz et al. US Publication No. 2016/0228371 A1 published on August 11, 2016 (cited in the IDS received on 3/30/23), and Chi et al., “Excipients and their Effects on the Quality of Biologics”, 10 pages (2011).
For claim 16, with respect to a stable lyophilized formulation of an anti-cancer peptide prepared by lyophilizing an aqueous formulation comprising an anti-cancer peptide, wherein the peptide comprises an HDM-2 binding component, a membrane resident component, acetate, and mannitol, and wherein the formulation has a pH of about 4.0-6.0:
Pincus et al. teaches a cancer treatment composition comprising an HDM-2 binding component and a membrane resident component where the two components are attached to each other (See Pincus, [0009], [0032], [0038]-[0039]). This composition has selectivity and a high affinity for cancer cells (See Pincus, [0038]). A specific species of the cancer treatment composition is termed PNC-27, which contains instant SEQ ID NO: 1 as the HDM-2 binding component and instant SEQ ID NO: 25 as the membrane resident component (See Pincus, [0041]-[0043], Table 1). As such, Pincus’s PNC-27 constitutes a specific species of anti-cancer peptide comprising an HDM-2 binding component attached (i.e., fused) to a membrane resident component as recited in instant claim 16. Furthermore, Pincus et al. teaches that formulations of the fusion peptide can be in the form of an aqueous solution or in a lyophilized form (See Pincus, [0065]). As such, the teachings of Pincus satisfy the claim limitation with respect to a lyophilized formulation of an anti-cancer peptide comprising an HDM-2 binding component attached (i.e., fused) to a membrane resident component as recited in instant claim 16.
With respect to how the lyophilized formulation is prepared, it is noted that the instant specification defines “lyophilized” as a state of a substance that has been subjected to a drying procedure where at least 50% of moisture has been removed (See instant, pg. 27, 4th paragraph). As such, the claimed lyophilized formulation being prepared from an aqueous formulation can include water. It is further noted that the lyophilization of an aqueous formulation comprising the anti-cancer peptide, acetate, and mannitol constitutes a product-by-process. Regarding product-by-process claims, the Federal Circuit has found that "[e]ven through product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim in the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." See MPEP 2113 and In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). Furthermore, the Federal Circuit found that “[b]ecause validity is determined based on the requirements of patentability, a patent is invalid if a product made by the process recited in a product-by-process claim is anticipated by or obvious from prior art products, even if those prior art products are made by different processes.” See MPEP 2113 and Amgen, Inc. v. F. Hoffman-La Roche Ltd., 580 F.3d 1340, 1370 n 14, 92 USPQ2d 1289, 1312, n 14 (Fed. Cir. 2009). In the instant case, the method by which the lyophilized formulation is prepared requires the resulting lyophilized formulation to comprise water (i.e., aqueous), the anti-cancer peptide comprising an HDM-2 binding component and a membrane resident component, acetate and mannitol. As such, the process by which the lyophilized formulation is made imparts structure with respect to the components of the formulation which are lyophilized and where the formulation form is in a lyophilized form. However, the actual process step of lyophilization does not need to be expressly taught by a reference. As discussed supra, Pincus et al. teaches that the formulation can be in a lyophilized form.
Pincus et al. also teaches that the pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (See Pincus, [0056]). Typical carriers include a solvent or dispersion medium containing, e.g., water buffered aqueous solutions, i.e., biocompatible buffers, ethanol, polyols such as glycerol, suitable mixtures thereof, surfactants or vegetable oils (See Pincus, [0056]). Furthermore, Pincus et al. teaches that the formulations can utilize conventional diluents, carriers, or excipients, etc., for example, one or more of a stabilizer, a surfactant, and optionally a salt and/or buffering agent (See Pincus, [0065]). As such, although Pincus et al. does not expressly teach preparing a lyophilized formulation by lyophilizing an aqueous solution comprising the anti-cancer peptide, given that Pincus et al. teaches that the formulation can be in a lyophilized form thereby constituting where such a form must have undergone the process of lyophilization and suggest water as a suitable pharmaceutical carrier, e.g., water buffered aqueous solutions, the teachings of Pincus et al. suggest utilizing a water buffered aqueous solution that is lyophilized. Thus, the teachings of Pincus et al. suggest lyophilizing a water buffered aqueous solution comprising the anti-cancer peptide thereby satisfying the claim limitations with respect to an aqueous solution comprising the anti-cancer peptide that is then lyophilized as recited in instant claim 16.
However, Pincus et al. does not expressly teach where acetate in a concentration of 1.36 mg/ml is the buffer, mannitol in a concentration of 40 mg/ml and sucrose in an amount of 20% as stabilizers, the concentration of the anti-cancer peptide is 25 mg/ml, the pH of the lyophilized formulation is 5.1, polysorbate 20 in an amount of 0.1% as a surfactant, and NaCl as a salt.
Schultz et al. teaches a lyophilization process which is separate from a primary container (See Schultz, [0010]). This lyophilization process leads to a lyophilized formulation (solid units) from a liquid solution via vacuum sublimation that is not only stable, but also provides patient convenience given that the lyophilized formulations or solid units can be placed in non-vial primary contains such as syringes or patch pumps (See Schultz, [0010], [0152], [0326]). The liquid solution would comprise about 20 mg/ml to about 200 mg/ml of the therapeutic peptide or protein prior to lyophilization (See Schultz, [0063], [0072]), and thus, Applicant’s elected concentration of anti-cancer peptide of 25 mg/ml lies within Schultz’s concentration of the therapeutic peptide or protein. The stable compositions, which Schultz refers to as solid units, comprise a therapeutic agent, particularly, a therapeutic protein such as an antibody, DVD-Ig, protein or peptide, and a stabilizer (See Schultz, [0013], [0100], [0157], [0327]). Schultz et al. defines a “stable” solid unit as a solid unit in which the therapeutic agent essentially retains its physical and/or chemical stability and/or biological activity (See Schultz, [0115]). Despite having a high proportion of sugar, the solid units maintain structural rigidity and resist changes in shape and/or volume when stored under ambient conditions for extended periods of time and maintain long-term physical and chemical stability of the protein without significant degradation and/or aggregate formation (See Schultz, [0013], [0158]-[0159], [0189]). The solid units advantageously exhibit uniform shape and free-flowing over conventional lyophilized formulations making Schultz’s lyophilized formulations easier to reconstitute, manipulate and use to manufacture a drug product (See Schultz, [0013], [0357]). Thus, the teachings of Schultz et al. suggest a lyophilized formulation that is stable by the inclusion of one or more stabilizers thereby suggesting a stable lyophilized formulation as recited in instant claim 16.
Regarding mannitol and sucrose, Schultz et al. defines a “stabilizer” as an excipient which inhibits, prevents, slows down, or reduces the degradation of a protein in a solid unit as compared to the protein in a solid unit without the stabilizer (See Schultz, [0137]). The stabilizer in the lyophilized formulation can be a sugar such as sucrose, mannitol, or trehalose (See Schultz, [0027]-[0028], [0065], [0157], [0327]). A sugar can also be considered a lyoprotectant, which is a species of stabilizer that is used to protect a protein during the lyophilization process (See Schultz, [0139], [0189]). As such, Schultz et al. teaches a stable solid unit comprising a lyophilized mixture of a therapeutic agent, e.g., a protein or peptide, and an amount of sucrose, sorbitol or trehalose which prevents or reduces chemical or physical instability of the therapeutic agent upon lyophilization and subsequent storage (See Schultz, [0028], [0189]). In one embodiment, Schultz et al. teaches that the solid units are prepared from a solution comprising about 10 to about 40 mg/ml of mannitol and about 60 mg/ml to about 80 mg/ml of sucrose (See Schultz, [0033], [0180], [0344]). In a further embodiment, the concentration of sucrose in a solution for preparation of the solid unit is less than 20% (See Schultz, [0034], [0344]). As such, Schultz et al. suggests lyophilizing a liquid solution comprising a therapeutic protein or peptide, mannitol in a concentration of about 10 to about 40 mg/ml and sucrose in an amount of less than 20% where the inclusion of mannitol and sucrose in these amounts protect a protein during the lyophilization process by inhibiting, preventing, slowing down, or reducing the degradation of a protein thereby constituting the inclusion of mannitol as recited in instant claim 16 and constituting Applicant’s species election of 40 mg/ml of mannitol and 20% sucrose.
Regarding buffers and pH, Schultz et al. defines a “buffer” as an agent(s) in a solution that allows the solution to resist changes in pH by the action of its acid-base conjugate components such as acetate, e.g., sodium acetate (See Schultz, [0140]). A buffer can provide a solution with a pH in the range from about 4 to about 8, from about 4.5 to about 7, or from about 5.0 to about 6.5 (See Schultz, [0140]). In Example 2, study 2, Schultz et al. examined the impact of sucrose on the stability of an antibody in solid units comprising a citrate/phosphate buffer and the impact of pH (See Schultz, [0544], [0552]). Schultz et al. notes that one challenge with lyophilizing a protein contained in a buffer matrix is the potential for specific buffer salts to precipitate during the freezing step resulting in large pH modifications that can negatively affect protein stability (See Schultz, [0545]). For example, a pH<4 can result from the crystallization of the dibasic form of sodium (See Schultz, [0545]). In Example 2, study 2, sucrose was added to the antibody liquid solution prior to freezing and the solution had a pH of 5.0 or 6.0 (See Schultz, [0546], [0553]). Schultz et al. found that even in the presence of additional excipients (e.g., buffer and NaCl) thereby constituting where NaCl is included in the lyophilized formulation, which are traditionally omitted for lyophilization, the antibody within the solid unit remained stable (See Schultz, [0623]). Moreover, in Example 18, Schultz et al. examined the stability of an DVD-Ig formulation comprising 20 mM acetate, 7% sucrose, 0.01% polysorbate 80 at a pH of 5.0 (See Schultz, [0700]; Table 44). As such, converting 20 mM acetate into mg/ml results in 1.18 mg/ml acetate (i.e., (MW of acetate at 59.04, x 20 mM)/1000). Thus, Schultz et al. suggests that the liquid solution to be lyophilized can further contain a buffer such as acetate in a concentration of 1.18 mg/ml where the pH should be in the range of about 5.0 to 6.5 thereby constituting the inclusion of acetate and where the pH overlaps with the claimed pH range of 4.0 to 6.0 as recited in instant claim 16, and constituting Applicant’s species elections where the suggested concentration of acetate at 1.18 mg/ml is close to the elected concentration of 1.36 mg/ml, where the elected pH of 5.1 lies within the suggested pH range of the lyophilized formulation of 5.0 to 6.5, and where the lyophilized formulation contains NaCl.
Regarding a surfactant, Schultz et al. defines a “surfactant” as an agent that protects a protein from air/solution interface-induced stresses, solution/surface induced stresses, to reduce aggregation of the protein, or to minimize the formation of particulates in the formulation such as nonionic surfactants such as polysorbate 20 (Tween 20) (See Schultz, [0141]). In one embodiment, the solid unit comprises a surfactant, e.g., a polysorbate (See Schultz, [0181]). In the Examples, Schultz et al. utilized polysorbate 80 in an amount of about 0.01% (See Schultz, Table 1 and 44). Thus, Schultz et al. suggests that the liquid solution to be lyophilized can further contain a surfactant such as polysorbate 20 in an amount of about 0.01% thereby constituting Applicant’s elected species of polysorbate 20.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the teachings of Pincus et al. and lyophilize a water buffered aqueous solution comprising PNC-27 as the anti-cancer peptide in a concentration of ranging from about 20 mg/ml to about 200 mg/ml, acetate as a buffer in a concentration of 1.18 mg/ml, mannitol as a stabilizer in a concentration ranging from about 10 to about 40 mg/ml, sucrose as a stabilizer in an amount of less than 20%, NaCl, and polysorbate 20 as a surfactant in an amount of 0.01% and where the formulation has a pH ranging from 5.0 to 6.5 thereby resulting in a stable lyophilized formulation with maintained structural rigidity and resistant to changes in shape and/or volume when stored under ambient conditions for extended periods of time and with maintained long-term physical and chemical stability of the anti-cancer peptide without significant degradation and/or aggregate formation. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because lyophilizing liquid solutions comprising a therapeutic protein or peptide in a concentration of ranging from about 20 mg/ml to about 200 mg/ml, acetate as a buffer in a concentration of 1.18 mg/ml, mannitol as a stabilizer in a concentration ranging from about 10 to about 40 mg/ml, sucrose as a stabilizer in an amount of less than 20%, NaCl, and polysorbate 20 as a surfactant in an amount of 0.01% and where the formulation has a pH ranging from 5.0 to 6.5 was known to result in a stable lyophilized formulation with maintained structural rigidity and resistant to changes in shape and/or volume when stored under ambient conditions for extended periods of time and with maintained long-term physical and chemical stability of the anti-cancer peptide without significant degradation and/or aggregate formation as taught by Schultz et al.
One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the PNC-27 as an anti-cancer peptide of Pincus et al. was formulated as a water buffered aqueous solution or in a lyophilized form in combination with one or more of a stabilizer, a surfactant, and optionally a salt and/or buffering agent. Therefore, substituting mannitol in a concentration ranging from about 10 mg/ml to about 40 mg/ml and sucrose in an amount of less than 20% as stabilizers, acetate in a concentration of 1.18 mg/ml as a buffering agent, polysorbate 20 in an amount of 0.01% as a surfactant, and NaCl as a salt where the formulation as a pH ranging from 5.0 to 6.5 would support the lyophilization of Pincus’s formulation thereby resulting in a stable lyophilized formulation with maintained structural rigidity and resistant to changes in shape and/or volume when stored under ambient conditions for extended periods of time and with maintained long-term physical and chemical stability of the anti-cancer peptide without significant degradation and/or aggregate formation by constituting the simple substitution of one known element for another to obtain predictable results and/or some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Additionally and/or alternatively, regarding the lyophilized formulation being “stable”, although the combination of Pincus et al. and Schultz et al. suggest a stable lyophilized formulation such that the inclusion of the specific components discussed supra result in a lyophilized formulation with maintained structural rigidity and resistant to changes in shape and/or volume when stored under ambient conditions for extended periods of time and with maintained long-term physical and chemical stability of the anti-cancer peptide without significant degradation and/or aggregate formation, the lyophilized formulation being stable is a functional property of the formulation that would necessarily be present given that the combination of references suggest the required structural limitations. Thus, the claiming of a new use, new function or unknown property which is necessarily present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact necessarily in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).
Additionally, regarding the concentrations/amounts/pH that overlap, MPEP 2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges discloses by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%". The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.) Moreover, the Federal Circuit found that a prima facie case existed where a claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms and the prior art taught that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." In re Geisler, 116 F.3d 1465, 1469-82, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997). Therefore, the elected concentration of the anti-cancer peptide would have been obvious to one of ordinary skill in the art since the elected concentration (i.e., 25 mg/mL) lies within the prior art concentration range of therapeutic protein or peptide (i.e., 20 mg/mL to 200 mg/mL); the elected concentration of mannitol would have been obvious to one of ordinary skill in the art since the elected concentration (i.e., 40 mg/ml) lies within the prior art concentration range of mannitol (i.e., about 10 mg/ml to about 40 mg/ml); and the elected pH of the lyophilized formulation would have been obvious to one of ordinary skill in the art since the elected pH (i.e., 5.1) lies within the prior art pH range of the lyophilized formulation (i.e., 5.0 to 6.5).
Regarding the concentration/amounts that are close, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metal Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Court held a proper rejection of a claim directed toward an alloy of having "0.8% nickel, 0.3% molybdenum, 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium.) Therefore, the elected concentration of acetate would have been suggested to one skilled in the art since the elected concentration (i.e., 1.36 mg/ml) is close to the prior art concentration of acetate (i.e., 1.18 mg/ml); and the elected amount of sucrose would have been suggested to one skilled in the art since the elected amount (i.e., 20%) is close to the prior art amount of sucrose (i.e., less than 20%).
For claim 16, with respect to where the lyophilized formulation comprises polysorbate 20 in an amount of 0.1% as elected:
As discussed supra, Pincus et al. teaches that the anti-cancer formulation can comprise a surfactant. Schultz et al. teaches that a stable, lyophilized formulation can comprise polysorbate 20 as a surfactant where an amount of the surfactant can be 0.01%. However, Pincus et al. and Schultz et al. do not expressly teach that the amount of surfactant can be 0.1%.
Chi teaches that non-ionic surfactants are widely used to stabilize proteins, suppress aggregation, and assist in protein refolding (See Chi, pg. 4, 3rd paragraph). Polysorbate 80 and 20 have been widely incorporated in marketed protein pharmaceuticals at 0.0003-0.3% range (See Chi, pg. 4, 3rd paragraph). As such, the surfactant amount taught by Schultz et al. lies within the range taught by Chi. Thus, an ordinary skilled artisan would be motivated to optimize the amount of polysorbate 20 from 0.01% to 0.1% as further articulated below.
The amount of polysorbate 20 in the lyophilized formulation is clearly a result specific parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal amount of polysorbate 20 in the lyophilized formulation needed to achieve the desired results. Thus, an ordinary skilled artisan would have been motivated to adjust the amount of polysorbate 20 in the lyophilized formulation, such as those taught by Schultz et al. and Chi, for improving the stability of the anti-cancer peptide in the lyophilized formulation by stabilizing the anti-cancer peptide, suppressing its aggregation, and assisting in its refolding, because an ordinary skilled artisan would have been able to utilize the teachings of Schultz et al. and Chi to obtain various amount parameters with a reasonable expectation of success. Thus, absent some demonstration of unexpected results from the claimed parameters, the optimization of the amount of polysorbate 20 in the lyophilized formulation would have been obvious at the time of applicant's invention. Therefore, the claimed invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, because the combined teachings of the prior art are fairly suggestive of the claimed invention.
For claims 16-19, with respect to where the formulation is reconstitutable with a liquid to become a particle-free solution containing about 20-30 mg/ml concentration of the anti-cancer peptide and no particles greater than about 2.0 nm, about 3.0 nm, or about 5.0 nm within about 2 minutes or less:
As discussed supra, Pincus et al. teaches that the pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (See Pincus, [0056]). Thus, Pincus et al. suggests reconstituting a sterile powder for an injectable solution.
Furthermore, as discussed supra, Schultz et al. teaches a liquid solution comprising 20-200 mg/ml of a therapeutic protein or peptide prior to lyophilization (See Schultz, [0063], [0072]). Schultz et al. teaches that the solid units remain free-flowing when stored under ambient conditions for extended periods of time, and yet are easily dissolved in a diluent, e.g., water (e.g., the solid units require minimal mixing when contacted with a diluent for reconstitution) (See Schultz, [0013], [0030], [0060]-[0061]). Moreover, Schultz et al. defines a “reconstituted” formulation as one which has been prepared by dissolving a lyophilized formulation containing a solid unit in a diluent such that the solid unit (and protein contained therein) is dispersed in the reconstituted formulation (See Schultz, [0109]). Diluents include sterile water, bacteriostatic water for injection, a pH buffered solution, sterile saline solution or dextrose solution (See Schultz, [0110]).
However, it is noted that the lyophilized formulation being reconstitutable with a liquid constitutes the intended use of the lyophilized formulation and once reconstituted with a liquid it become a particle-free solution comprising about 20-30 mg/ml of the anti-cancer peptide and no particles greater than about 2.0 nm, about 3.0 nm, or about 5.0 nm within about 2 minutes or less constitutes a functional and/or physical property of the reconstituted formulation. Pursuant to MPEP 2111.04(I), [c]laim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. However, examples of claim language, although not exhaustive, that may raise a question as to the limiting effect of the language in a claim are:
(A) "adapted to" or "adapted for" clauses;
(B) "wherein" clauses; and
(C) "whereby" clauses.
The court has found that the determination of whether clauses such as “wherein” and “whereby" is a limitation in a claim is dependent on the specific facts of the case. If the “wherein" or “whereby” clause limits a process claim where the clause gives meaning and purpose to the manipulative steps, it should be given patentable weight. Griffin v. Bertina, 285 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002). However, the court also found (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” In the instant case, the claimed lyophilized formulation is intended to be capable of reconstitution (i.e., reconstitutable) with a liquid where such reconstitution would result in a particle-free solution comprising about 20-30 mg/ml of the anti-cancer peptide and no particles greater than about 2.0 nm, about 3.0 nm, or about 5.0 nm within about 2 minutes or less thereby constituting functional and/or physical properties of the reconstituted formulation. Although it would appear that structure is imparted by such a use and/or properties, i.e., the formulation is dissolved in a liquid such that the concentration of the anti-cancer peptide is 20-30 mg/ml and there are no particles greater than about 2.0 nm, about 3.0 nm, or about 5.0 nm, the structural limitations are not structural limitations of the lyophilized formulation. Rather, the structural limitations are of the reconstituted solution, which is not claimed. Furthermore, the time it takes for the lyophilized formulation to dissolve is not a structural limitation of the lyophilized formulation. Since the combination of Pincus et al. and Schultz et al. suggest the lyophilized formulation as discussed supra, the suggested lyophilized formulation would necessarily result in a lyophilized formulation capable of being reconstituted with a liquid where such reconstitution would necessarily result in a particle-free solution comprising about 20-30 mg/ml of the anti-cancer peptide and no particles greater than about 2.0 nm, about 3.0 nm, or about 5.0 nm within about 2 minutes or less. Therefore, the combined teachings of Pincus et al. and Schultz et al. satisfy the claim limitation with respect to where the formulation is reconstitutable with a liquid to become a particle-free solution containing about 20-30 mg/ml concentration of the anti-cancer peptide and no particles greater than about 2.0 nm, about 3.0 nm, or about 5.0 nm within about 2 minutes or less as recited in instant claims 16-19.
For claims 22-24, with respect to where less than about 1% of the anti-cancer peptide is degraded after about 2 years, about 3 years, or about 5 years of storage at about 2-8°C:
Pincus et al. does not expressly teach or suggest the physical and/or chemical stability/integrity of the lyophilized formulation comprising the anti-cancer peptide.
Schultz et al. teaches that the amount of sucrose or trehalose needed in the lyophilized formulation is an amount sufficient to maintain the stability of the protein for at least 12 months of storage at about 25°C (See Schultz, [0029], [0048], [0169]-[0170]-[0173]). In one embodiment, Schultz et al. teaches that the stability of the protein within a solid unit is determined using SEC to determine the percentage of monomer protein in a reconstituted solution where the protein is considered stable if there is a low percentage of degraded and/or aggregated protein or a high level (e.g., 98%, 99% or 99.5% or more) of monomer protein (See Schultz, [0115]-[0120], [0171]).
However, although Pincus et al. and Schultz et al. do not expressly examine the stability of the anti-cancer peptide after about 2, 3, or 5 years of storage at about 2-8°C, since the combination of Pincus and Schultz suggest the structural limitations of the stable lyophilized formulation, the physical/functional property of the stable lyophilized formulation (i.e., less than about 1% of the anti-cancer peptide is degraded after about 2, 3, or 5 years of storage at about 2-8°C) of the claimed stable lyophilized formulation and the suggested stable lyophilized formulation would necessarily read upon the same. The discovery of a previously unappreciated property of a prior art composition, or a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer. Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new physical/functional property (i.e., less than about 1% of the anti-cancer peptide is degraded after about 2, 3, or 5 years of storage at about 2-8°C) which would necessarily read upon the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 4333 (CCPA 1977). Therefore, the combined teachings of Pincus and Schultz satisfy the claim limitations as recited in instant claims 22-24.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Conclusion
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/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654