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 .
DETAILED ACTION
Claims 1, 4-10, 12-17, 20-23, 30-33, 70, 102, and 138 are pending. Claims 18-19 is now cancelled. Claims 2-3, 11, 24-29, 34-69, 71-101, 103-137, and 139 were previously cancelled. Claim 33 is withdrawn. Claims 1, 4-10, 12-17, 20-23, 30-32, 70, 102, and 138 are under examination on their merits.
Response to Arguments
Applicant's arguments filed 3/27/2026 have been fully considered but they are not persuasive.
Applicant argues against the rejection of claims under 35 U.S.C. 103 on the grounds that the person of ordinary skill in the art would not have expected such a high-mass dose could be delivered subcutaneously while maintaining the stability of the composition. Applicant argues that the lower bound of the claimed range of imetelstat sodium dose (1500 mg) is nearly 27% higher than the calculated upper bound for men, thus the massive change requires non-obvious formulation adjustments to maintain solubility and activity (Arguments, paragraphs 1-2 on page 10). Applicant argues that Bookbinder teaches a pharmaceutical unit dosage form from about 1 mg to about 1000 mg for subcutaneous administration (Arguments, paragraph 1 on page 11). Applicant argues further that Bookbinder does not teach compatibility and stability of imetelstat or imetelstat sodium co-mixed with rHuPH20 or a variant or fragment of PH20 hyaluronidase enzyme (Arguments, second to last paragraph on page 11). Applicant argues that the compatibility and stability of imetelstat with a hyaluronidase would not have been predictable because of the amphiphilic architecture of imetelstat (Arguments, paragraph 1 on page 13).
In response, Bookbinder is not relied on to teach the dose of imetelstat sodium in the composition, thus Bookbinder’s teachings regarding dosage are not relevant to the rejection. Regarding the compatibility and stability of imetelstat or imetelstat sodium co-mixed with a hyaluronidase enzyme, Applicant has not presented any non-obvious structural differences in the formulation to differentiate from the prior art. If the formulation of an amphiphilic molecule such as imetelstat requires unique formulation, then any non-obvious structural differences should be incorporated into the structure of the claimed composition.
Applicant argues further against the rejection of claims under 35 U.S.C. 103 on the grounds that Favre injects the hyaluronidase before the DNA, so the person of ordinary skill in the art would not have had a reasonable expectation of success for a co-formulation where a naked, lipidated oligonucleotide is in direct molecular contact with the enzyme (Arguments, bottom paragraph on page 15). Applicant argues further that Fayad’s teachings pertain to modified di-and tri-saccharides rather than the claimed 13-mer polymer (paragraph 1 on page 16).
This argument is not persuasive. First, neither Favre nor Fayad is relied on in any prior art rejection of record. Fayad was merely cited as evidence that the 2-deoxy modification present in DNA, which is part of imetelstat, does not inhibit hyaluronidase. Applicant has not provided any objective evidence that the person of ordinary skill in the art would have expected incompatibility between any portion of imetelstat and hyaluronidase. Applicant has only pointed to a silence in the prior art with respect to the combination of hyaluronidase with an amphiphilic macromolecule. There is no teaching away in the prior art between the combination of an amphiphilic macromolecule and hyaluronidase and Applicant has not provided any chemical rationale as to why the person of ordinary skill in the art would have expected incompatibility between the hyaluronidase and a nucleic acid, a lipid, or an amphiphilic macromolecule.
Applicant argues further against the rejection of clams under 35 U.S.C. 103 on the grounds that the therapeutically effective pharmacokinetic profile would not have been predictable based upon the teachings of Frost because Frost describes systemic bioavailability of larger protein molecules rather than the lipid-linked oligonucleotide imetelstat (Arguments, first full paragraph on page 17).
This argument is unpersuasive. The increased bioavailability (i.e. improved pharmacokinetic profile) of drugs administered subcutaneously in combination with hyaluronidase is a result of the mechanism of action of hyaluronidase. Bookbinder teaches that human soluble PH20 hyaluronidase glycoproteins open channels in the interstitial space through degradation of glycosaminoglycans (column 8, lines 2-5) and that these channels facilitate the diffusion of small molecules, proteins, and nucleic acids less than 500 nm in size (column 8, lines 6-10). Applicant has not provided any convincing evidence to suggest that the hyaluronidase in combination with imetelstat works any differently than the hyaluronidase in combination with a protein.
Applicant argues further against the rejection of claims under 35 U.S.C. 103 on the grounds that the role of histidine in Soane is limited to viscosity reduction in therapeutic proteins, for example, monoclonal antibodies (Arguments, paragraph bridging bottom of page 18 through top of page 19).
This argument is unpersuasive because Soane teaches use of histidine as a buffer to maintain the pH at 6.0 (paragraph 115, Example 1, line 27 and line 30) and Bookbinder teaches that the activity of hyaluronidase is optimal at acidic to neutral conditions (Bookbinder column 25, lines 57-61). Furthermore, Stuart teaches that the telomerase inhibitor is administered as an aqueous solution with dissolution enhancers including amino acids (column 32, lines 42-46). The rejection does not require reducing viscosity of the composition.
With respect to the nonstatutory double patenting rejections of record, Applicant does not present any new arguments not already addressed above.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 for establishing a background for determining obviousness under 35 U.S.C. 103 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 the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The following rejections are necessitated by the amendment.
Claims 1, 4-9, 12-17, 20-23, 30-32, and 138 are rejected under 35 U.S.C. 103 as being unpatentable over Stuart et al. (US 9,375,485 B2; cited in the Non-Final Action mailed on 12/30/2022) in view of Bookbinder et al. (US 7,767,429 B2; cited in the Non-Final Action mailed on 12/30/2022), Frost et al. (Expert opinion on drug delivery 4.4 (2007): 427-440; cited in the Non-Final Action mailed on 4/24/2024), and Soane et al. (WO 2020/112855 A1; IDS filed 9/8/2022) and as evidenced by Hanczyc et al. (Langmuir, 2012, Vol. 28, pp. 6662−6669; cited in the Non-Final Action mailed on 12/30/2022) and by Centers for Disease Control (2021, website; cited in the Non-Final Action mailed on 12/30/2022).
Stuart teaches a telomerase inhibitor comprising an oligonucleotide (column 4, lines 12-14) further comprising a lipid moiety linked to the 5' and/or 3' end of the oligonucleotide (column 4, lines 24-27). Stuart teaches a method for reducing neoplastic progenitor cell proliferation in an individual diagnosed with or suspected of having myelofibrosis or myelodysplastic syndrome comprising administering a telomerase inhibitor (Stuart claim 6) comprising an oligonucleotide, wherein the oligonucleotide further comprises a lipid moiety linked to the 5' and/or 3' end of the oligonucleotide (Stuart claims 11 and 17). The composition may be injected subcutaneously (column 32, lines 46-47). In lines 32-34 of column 4, Stuart teaches that the telomerase inhibitor is imetelstat. Stuart teaches that a telomerase inhibitor composition may be formulated in a unit dosage form (column 22, lines 48-49 and column 23, lines 19-20).
Stuart does not teach that the composition comprises an effective amount of a recombinant human hyaluronidase enzyme, wherein the recombinant human hyaluronidase enzyme is rHuPH20 or a variant or fragment thereof.
Bookbinder teaches human soluble PH20 hyaluronidase glycoproteins or sHASEGPs (column 3, lines 51-54). Bookbinder teaches rHuPH20, which is a recombinant human hyaluronidase enzyme, in Example 14 (line 15 of column 97). Thus, Bookbinder’s sHASEGPs are soluble recombinant forms of human hyaluronidase PH20 (rHuPH20). Bookbinder teaches that subcutaneous administration of molecules in the presence of sHASEGPs facilitates their rapid systemic distribution (column 8, lines 30-33). Bookbinder teaches that sHASEGPs open channels in the interstitial space through degradation of glycosaminoglycans (column 8, lines 2-5) and that these channels facilitate the diffusion of small molecules, proteins, and nucleic acids less than 500 nm in size (column 8, lines 6-10). Bookbinder teaches further that temporary removal of glycosaminoglycans enhances the delivery of drugs into interstitial spaces, which facilitates diffusion of therapeutic molecules and proteins (column 8, lines 26-30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the telomerase inhibitor imetelstat of Stuart with the recombinant human hyaluronidase enzyme of Bookbinder (rHUPH20) in an effective amount to enhance systemic distribution of the telomerase inhibitor imetelstat for the treatment of cancer. One of ordinary skill in the art would have had a reasonable expectation of success given the teaching of Bookbinder that sHASEGPs (a species of hyaluronidase enzyme) facilitate the diffusion of many forms of therapeutic molecules and proteins, including small molecules, proteins, and nucleic acids, as long as they are less than 500 nm in size. Because the telomerase inhibitor of Stuart is an oligonucleotide comprising only 13 nucleotides (column 4, line 19 of Stuart) and a lipid moiety up to 16 carbons in length (column 4, lines 31-32 of Stuart), it would have been obvious to one of ordinary skill in the art that the oligonucleotide (the telomerase inhibitor imetelstat) of Stuart is less than the 500 nm size limit taught by Bookbinder, as evidenced by Hanczyc (Abstract: an oligonucleotide less than 60 bases is less than 20.4 nm in size).
Regarding the amount of telomerase inhibitor in the composition, Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg (lines 34-59 of column 34). Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 78 mg to 1014 mg (women) or from 91 mg to 1183 mg (men). The upper bound of the range for men is less than the lower bound of the instantly claimed range of about 1500 mg to about 3000 mg.
Stuart teaches that telomerase inhibitor compounds are effective over a wide dosage range and are generally administered in a therapeutically effective amount (Stuart, lines 32-34 of column 23). Stuart teaches: “It will be understood, however, that the amount of the telomerase inhibitor compounds actually administered will be determined by a physician, in light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms and the like” (Stuart, lines 32-41 of column 23). Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of imetelstat in the composition of Stuart modified by Bookbinder based on the variables taught by Stuart and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
The limitation “wherein the composition formulated for subcutaneous administration provides an effective pharmacokinetic profile for the telomerase inhibitor when co-formulated with the recombinant human hyaluronidase enzyme” is interpreted as further limiting the amount of the recombinant human hyaluronidase enzyme relative to imetelstat or imetelstat sodium.
Stuart and Bookbinder do not teach that the composition provides a therapeutically effective pharmacokinetic profile for the telomerase inhibitor when co-formulated with the recombinant human hyaluronidase enzyme.
Frost teaches that recombinant human hyaluronidase (rHuPH20) enables subcutaneous drug and fluid administration (Title). Specifically, Frost teaches that molecules up to several hundred nanometers in diameter are readily dispersed by co-administration with rHuPH20 and the pharmacokinetic profile of molecules co-injected with rHuPH20 results in a higher Cmax and earlier Tmax than when injected with carrier controls (page 437, right column, paragraph 3). Frost teaches that driving the pharmacokinetic profile from a traditional subcutaneous absorption curve towards an intravenous-like bolus profile may be valuable when peak blood levels and time to onset are critical to achieve the desired clinical response (page 438, right column, 5.2 Modified pharmacokinetics following subcutaneous injection with rHuPH20)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the amount of rHuPH20 in the composition of Stuart and Bookbinder such that the composition would have had an effective pharmacokinetic profile when administered subcutaneously. The person of ordinary skill in the art would have had a reasonable expectation of success based on the teaching of Frost, which suggests that rHuPH20 in combination with molecules up to several hundred nanometers in diameter confers favorable pharmacokinetics.
Stuart teaches that the telomerase inhibitor is administered as an aqueous solution with dissolution enhancers including amino acids (column 32, lines 42-46). However, Stuart does not teach that the amino acids are selected from methionine and histidine.
Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27). The concentration of histidine in the buffer is also 50 mM based on the 1:1 stoichiometry of histidine to hydrochloride. The adjusted pH of the buffered formulations is 6.0 (paragraph 115, line 30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to buffer the formulation of Stuart, Bookbinder, and Frost using the histidine hydrochloride buffer taught by Soane. One of ordinary skill in the art would have been motivated to use a slightly acidic buffer system (such as pH 6.0) based on the activity of the hyaluronidase enzyme, which has an optimal pH at acidic to neutral conditions (Bookbinder column 25, lines 57-61).
Pertaining to claims 4 and 7-8, Bookbinder teaches truncation of the hydrophobic C-terminus of recombinant human PH20 enzyme (column 86, Example 4, lines 7 and 18-20). Bookbinder teaches that the truncation may occur at residues P478, Q479, I480, F481, Y482 (column 87, lines 14-15), or N483 (column 86, line 64). Thus, Bookbinder teaches a fragment of the PH20 enzyme. One of ordinary skill in the art would have been motivated before the effective filing date of the claimed invention to use the truncated recombinant human PH20 enzyme taught by Bookbinder in the combination of hyaluronidase enzyme (Bookbinder) and the telomerase inhibitor imetelstat (Stuart) discussed above in order to improve the solubility of the combination by removing the hydrophobic tail of hyaluronidase enzyme, as taught by Bookbinder (column 86, Example 4, lines 7 and 18-20).
Pertaining to claims 5-6 and 9, Bookbinder claim 1 recites “a hyaluronidase glycoprotein that consists of the sequence of amino acids set forth as amino acids 1-477, 36-477, 1-478, 36-478, 1-479, 36-479, 1-480, 36-480, 1-481, 36-481, 1-482, 36-482, 1-483 or 36-483 of 40 SEQ ID NO: 1,” wherein SEQ ID NO: 1 is 100% identical to the instant SEQ ID NO: 1, which represents the amino acid sequence of PH20. Thus, Bookbinder teaches N-terminal truncations of PH20 with a cleavage position before amino acid residue L36 and specifically teaches the PH20 fragment of 36-482. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the N-terminal truncations of PH20 taught by Bookbinder in the combination of Stuart, Bookbinder, Frost, and Soane. One of ordinary skill in the art would have recognized that the N-terminal leader sequence would not have been required for the enzymatic activity of the PH20 enzyme because the leader sequence would have been removed during cellular production prior to purification, as taught by Bookbinder (Example 9, Purification of sHASEGP, column 93, lines 4-6).
Pertaining to claims 12-13, Bookbinder teaches an embodiment in which a hyaluronidase domain of a sHASEGP polypeptide, or a catalytically active portion thereof, does not include the entire sequence of amino acids set forth in SEQ ID NO: 1 but is at least 90% or 95% identical to SEQ ID NO: 1 (column 6, lines 25-29), wherein SEQ ID NO: 1 of Bookbinder is identical to the instant SEQ ID NO: 1 (the amino acid sequence of wild-type PH20).
Regarding claim 14, Bookbinder teaches unit dosage forms of a hyaluronidase enzyme, such as 1 to 5,000 Units of the enzyme in a small volume (column 59, lines 31-33) that are suitable for administration to a human (column 59, lines 9-12). 1 to 5,000 Units of a hyaluronidase enzyme overlaps with 100 U to 50,000 U. Bookbinder also teaches that the unit dosage (1 to 5,000 units of the enzyme) can be prepackaged in a syringe for use, such as after viscoelastic injection (column 59, lines 34-35), which is a form of subcutaneous injection. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine a unit dosage of a hyaluronidase enzyme at a known and tolerated dosage acceptable for subcutaneous administration in a human with the imetelstat of Stuart in order to facilitate diffusion of imetelstat. One of ordinary skill in the art would have had a reasonable expectation of success given that the dosage of hyaluronidase enzyme taught by Bookbinder is formulated for subcutaneous administration.
Pertaining to claim 15, Stuart teaches that the telomerase inhibitor is administered with a pharmaceutically acceptable excipient (column 4, lines 34-36).
Pertaining to claim 16 -17, Stuart teaches that the telomerase inhibitor is administered as an aqueous solution with dissolution enhancers including 10% dextrose (a saccharide). A 10% dextrose solution (i.e. 10 g/100 mL) is approximately 555 mM of saccharide, which is slightly above the claimed range of 10 mM to 500 mM. Therefore, a prima facie case of obviousness exists. See MPEP 2144.05.
Pertaining to claim 20, Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27), which is within the claimed range.of from 1 mM to 100 mM.
Pertaining to claim 21, Stuart teaches that the telomerase inhibitor is administered with a buffer (column 33, lines 7-8).
Pertaining to claims 22-23, Bookbinder teaches that sHASEGP glycoproteins (human hyaluronidase enzymes) are neutral active in vitro at pH between 5 and 8 under conditions of salt less than 150 mM and buffering strength less than 50 mM (column 25, lines 57-61). A buffering strength less than 50 mM overlaps with the claimed range of 1 to 100 mM. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to formulate a composition comprising both the rHuPH20 and a telomerase inhibitor at pH 5 to 8 in order to maintain the activity of the hyaluronidase enzyme. pH 5 to 8 overlaps with the claimed range of pH 3.0 to 9.0.
Regarding claim 30, Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg (lines 34-59 of column 34). The upper limit of Stuart’s range is less than the instantly claimed range of about 17.0 mg/kg to about 20 mg/kg.
Stuart also teaches that the telomerase inhibitor compounds are effective over a wide dosage range and that the amount of telomerase inhibitor compounds administered will be determined by a physician based on the chosen route of administration and other factors (age, weight, patient response, symptom severity). See lines 32-41 of column 23.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of imetelstat in the composition of Stuart modified by Bookbinder and Frost based on the variables taught by Stuart and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
Pertaining to claim 31, Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg (lines 34-59 of column 34). Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 78 mg to 1014 mg (women) or from 91 mg to 1183 mg (men). The upper bound of the range for men is less than the lower bound of the instantly claimed range of about 1500 mg to about 1600 mg.
Stuart also teaches that the telomerase inhibitor compounds are effective over a wide dosage range and that the amount of telomerase inhibitor compounds administered will be determined by a physician based on the chosen route of administration and other factors (age, weight, patient response, symptom severity). See lines 32-41 of column 23.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of imetelstat in the composition of Stuart modified by Bookbinder based on the variables taught by Stuart and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
In lines 45-46 and 65-66 of column 22, Stuart teaches that the active ingredient (the telomerase inhibitor imetelstat) may be lyophilized (claim 32) to provide the appropriate particle size prior to combining with other ingredients (lines 65-67column 22). Similarly, Bookbinder teaches that sHASEGP (a human hyaluronidase enzyme) may be prepared as a lyophilized powder (Bookbinder, column 65, lines 31-32) and that the lyophilized form is ideal for storage (Bookbinder lines 48-50 of column 55). Since both the telomerase inhibitor and the hyaluronidase enzyme may be prepared in lyophilized forms, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine Stuart’s telomerase inhibitor in lyophilized form with Bookbinder’s human hyaluronidase enzyme rHuPH20 in lyophilized form in order to formulate the composition for storage. The person of ordinary skill in the art would have had a reasonable expectation of success in the formulation of the lyophilized composition.
Regarding claim 138, Stuart does not teach that the telomerase inhibitor dosage is about 1500 mg to 2500 mg.
Stuart teaches that telomerase inhibitor compounds are effective over a wide dosage range and are generally administered in a therapeutically effective amount (Stuart, lines 32-34 of column 23). Stuart teaches: “It will be understood, however, that the amount of the telomerase inhibitor compounds actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms and the like” (Stuart, lines 32-41 of column 23).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of imetelstat in the composition of Stuart modified by Bookbinder and Frost based on the variables taught by Stuart and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Stuart in view of Bookbinder, Frost, and Soane and as evidenced by Hanczyc and Centers for Disease Control, as applied to claims 1, 4-9, 12-17, 20-23, 30-32, and 138 above, further in view of Pecceu et al. (Genes Vol. 97, 1991, pp. 23-258).
See discussion of Stuart, Bookbinder, Frost, and Soane above, which is incorporated into this rejection as well.
Bookbinder teaches enhanced mammalian expression systems using signal leaders capable of efficient secretion of sHASEGP (column 5, lines 51-53).
However, Stuart, Bookbinder, Frost, and Soane do not teach that the N-terminus of the PH20 fragment comprises a human growth hormone-derived signal peptide.
Pecceu teaches that human interleukin 1β fused to the human growth hormone signal peptide is secreted by Chinese hamster ovary cells (Title). The sequence of the human growth hormone signal peptide is given in Figure 1B and is identical to SEQ ID NO: 3 of the instant application. Fig. 2 demonstrates the signal peptide nucleotide sequence is fused to the N-terminus of the gene.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to further modify the rHuPH20 fragment in the composition of Stuart, Bookbinder, Frost, and Soane such that the enzyme could be produced in a mammalian expression system. One skilled in the art would have recognized that the secretion of the PH20 enzyme fragment would have required a signal peptide recognized by the expression system. One of ordinary skill in the art would have been motivated to use the human growth factor-derived signal peptide taught by Pecceu because of its demonstrated success in recombinant protein expression by Chinese hamster ovary cells.
Claims 70 and 102 are rejected under 35 U.S.C. 103 as being unpatentable over Stuart et al. (US 9,375,485 B2; cited in the Non-Final Action mailed on 12/30/2022) in view of Bookbinder et al. (US 7,767,429 B2; cited in the Non-Final Action mailed on 12/30/2022)and Soane and as evidenced by Hanczyc et al. (Langmuir, 2012, Vol. 28, pp. 6662−6669; cited in the Non-Final Action mailed on 12/30/2022) and by Centers for Disease Control (2021, website; cited in the Non-Final Action mailed on 12/30/2022).
See discussion of Stuart and Bookbinder above, which is incorporated into this rejection as well.
Stuart teaches that the telomerase inhibitor is administered as an aqueous solution with dissolution enhancers including amino acids (column 32, lines 42-46). However, Stuart does not teach that the amino acids are selected from methionine and histidine.
Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27). The concentration of histidine in the buffer is also 50 mM based on the 1:1 stoichiometry of histidine to hydrochloride. The adjusted pH of the buffered formulations is 6.0 (paragraph 115, line 30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to buffer the formulation of Stuart and Bookbinder using the histidine hydrochloride buffer taught by Soane. One of ordinary skill in the art would have been motivated to use a slightly acidic buffer system (such as pH 6.0) based on the activity of the hyaluronidase enzyme, which has an optimal pH at acidic to neutral conditions (Bookbinder column 25, lines 57-61).
Pertaining to claim 70, “for subcutaneous administration” is an intended use of the unit dosage form and does not further limit the structure of the claimed unit dosage form.
Stuart does not teach that the composition comprising imetelstat is in unit dosage form with rHuPH20.
However, Stuart teaches that a telomerase inhibitor composition may be formulated in a unit dosage form (column 22, lines 48-49 and column 23, lines 19-20). Bookbinder teaches that sHASEGP polypeptides (human hyaluronidase enzymes) may be formulated in unit dosage forms (column 58, lines 59 and 67 and column 59, line 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate a composition in unit dosage form comprising telomerase inhibitor imetelstat and an effective amount of the hyaluronidase enzyme rHuPH20 to enhance the systemic distribution of imetelstat. One of ordinary skill in the art would have recognized the benefit of formulating the composition in a unit dosage form for ease of administration to the subject. The person of ordinary skill in the art would have had a reasonable expectation of success in formulating the unit dosage form.
Regarding the amount of telomerase inhibitor in the composition in unit dosage form, Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg (lines 34-59 of column 34,). Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 78 mg to 1014 mg (women) or from 91 mg to 1183 mg (men). The upper bound of the range for men is less than the lower bound of the instantly claimed range of about 1500 mg to about 3000 mg.
Stuart also teaches that the telomerase inhibitor compounds are effective over a wide dosage range and that the amount of telomerase inhibitor compounds administered will be determined by a physician based on the chosen route of administration and other factors (age, weight, patient response, symptom severity). See lines 32-41 of column 23.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of imetelstat in the composition in unit dosage form of Stuart modified by Bookbinder based on the variables taught by Stuart and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
Regarding claim 102, “for subcutaneous administration” is an intended use of the kit and does not further limit the structure of the claimed kit.
Stuart does not teach that the composition comprising imetelstat is in a kit with rHuPH20. However, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate a composition in a kit comprising a telomerase inhibitor imetelstat and an effective amount of the hyaluronidase enzyme rHuPH20 to enhance the systemic distribution of imetelstat. One of ordinary skill in the art would have recognized the benefit of formulating the composition in a kit for the ease of retail to the customer (e.g. a medical clinic).
Regarding the amount of telomerase inhibitor in the composition in the kit, Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg (lines 34-59 of column 34,). Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 78 mg to 1014 mg (women) or from 91 mg to 1183 mg (men). The upper bound of the range for men is less than the lower bound of the instantly claimed range of about 1500 mg to about 3000 mg.
Stuart also teaches that the telomerase inhibitor compounds are effective over a wide dosage range and that the amount of telomerase inhibitor compounds administered will be determined by a physician based on the chosen route of administration and other factors (age, weight, patient response, symptom severity). See lines 32-41 of column 23.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of imetelstat in the composition in the kit of Stuart modified by Bookbinder based on the variables taught by Stuart and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
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.
The following rejections are necessitated by the amendment.
Claims 1, 4-9, 12-17, 20-23, 30-32, and 138 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-53 of U.S. Patent No. 9,375,485 (hereafter ‘485) in view of Bookbinder et al. (US 7,767,429 B2), Stuart et al. (US 20140163090 A1; hereafter Stuart PGPub), Frost et al. (Expert opinion on drug delivery 4.4 (2007): 427-440; cited in the Non-Final Action mailed on 4/24/2024), and Soane et al. (WO 2020/112855 A1; IDS filed 9/8/2022) and as evidenced by Hanczyc et al. (Langmuir, 2012, Vol. 28, pp. 6662−6669; cited in the Non-Final Action mailed on 12/30/2022) and by Centers for Disease Control (2021, website; cited in the Non-Final Action mailed on 12/30/2022).
Claim 1 of ‘485 is drawn to is drawn to method of alleviating at least one symptom associated with myelofibrosis (a rare blood cancer). The method comprises administering a clinically effective amount of a telomerase inhibitor to the individual (claim 1 of ‘485). Claims 2-53 of ‘485 further limit the method of administering a telomerase inhibitor.
Claim 11 of ‘485 recites that the telomerase inhibitor comprises an oligonucleotide. Claim 17 of ‘485 recites that the telomerase inhibitor comprises an oligonucleotide and a lipid moiety linked to the 5’ and/or 3’ end of the oligonucleotide.
Claim 14 of ‘485 limits the oligonucleotide to SEQ ID NO: 12.
Claims 18-19 of ‘485 specify a linker between the oligonucleotide and a lipid moiety.
Claim 20 of ‘485 limits the lipid moiety to a palmitoyl (C16) moiety.
Claim 21 of ‘485 limits the telomerase inhibitor to imetelstat.
Claim 23 of ‘485 recites that the telomerase inhibitor is formulated for subcutaneous administration.
Claim 40 of ‘485 recites that the oligonucleotide telomerase inhibitor comprises an oligonucleotide with at least one N3' ➔ P5' thiophosphoramidate internucleoside linkage.
Claims 1-53 of ‘485 do not recite that the composition further comprises an effective amount of rHuPH20.
Bookbinder teaches human soluble PH20 hyaluronidase glycoproteins or sHASEGPs (column 3, lines 51-54). Bookbinder teaches rHuPH20, which is a recombinant human hyaluronidase enzyme, in Example 14 (line 15 of column 97). Thus, Bookbinder’s sHASEGPs are soluble recombinant forms of human hyaluronidase PH20 (rHuPH20). Bookbinder teaches that subcutaneous administration of molecules in the presence of sHASEGPs facilitates their rapid systemic distribution (column 8, lines 30-33). Bookbinder teaches that sHASEGPs open channels in the interstitial space through degradation of glycosaminoglycans (column 8, lines 2-5) and that these channels facilitate the diffusion of small molecules, proteins, and nucleic acids less than 500 nm in size (column 8, lines 6-10). Bookbinder teaches further that temporary removal of glycosaminoglycans enhances the delivery of drugs into interstitial spaces, which facilitates diffusion of therapeutic molecules and proteins (column 8, lines 26-30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the telomerase inhibitor imetelstat of claims 1-53 of ‘485 with the hyaluronidase enzyme rHuPH20 of Bookbinder in an effective amount to enhance systemic distribution of the telomerase inhibitor for the treatment of cancer. One of ordinary skill in the art would have had a reasonable expectation of success given the teaching of Bookbinder that sHASEGPs (a species of hyaluronidase enzyme) facilitated the diffusion of many forms of therapeutic molecules and proteins, including small molecules, proteins, and nucleic acids, as long as they were less than 500 nm in size. Because the telomerase inhibitor of claims 1-53 of ‘485 is an oligonucleotide comprising only 13 nucleotides (claim 14 of ‘485) and lipid moiety up to 16 carbons in length (claim 20 of ‘485), it would have been obvious to one of ordinary skill that the oligonucleotide (the telomerase inhibitor imetelstat) of Stuart is less than the 500 nm size limit taught by Bookbinder, as evidenced by Hanczyc (see Abstract of Hanczyc: an oligonucleotide less than 60 bases is less than 20.4 nm in size).
Claims 1-53 of ‘485 do not recite that the composition comprises 1500 mg to 3000 mg of imetelstat in unit dosage form.
Stuart PGPub teaches a method of treating myelofibrosis by administering imetelstat (see Stuart PGPub claims 9-10 and 30). In [0142], Stuart PGPub teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg. Stuart PGPub teaches that a telomerase inhibitor composition may be formulated in a unit dosage form ([0081] and [0084]). Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart PGPub teaches that the telomerase inhibitor may be administered in a range of dosages from 78 mg to 1014 mg (women) or from 91 mg to 1183 mg (men). The upper bound of the range for men is less than the instantly claimed range of about 1500 mg to about 3000 mg.
Stuart teaches that telomerase inhibitor compounds are effective over a wide dosage range and are generally administered in a therapeutically effective amount ([0085]). Stuart teaches: “It will be understood, however, that the amount of the telomerase inhibitor compounds actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms and the like” ([0085]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of imetelstat in the composition, as suggested by Stuart PGPub, in the method of claims 1-53 of ‘485 modified by Bookbinder and Stuart PGPub. The person of ordinary skill in the art would have had a reasonable expectation of success in optimizing the dosage of imetelstat for subcutaneous administration with hyaluronidase.
Claims 1-53 of ‘485 do not recite and Stuart PGPub and Bookbinder do not teach that the composition provides a therapeutically effective pharmacokinetic profile for the telomerase inhibitor when co-formulated with the recombinant human hyaluronidase enzyme.
Frost teaches that recombinant human hyaluronidase (rHuPH20) enables subcutaneous drug and fluid administration (Title). Specifically, Frost teaches that molecules up to several hundred nanometers in diameter are readily dispersed by co-administration with rHuPH20 and the pharmacokinetic profile of molecules co-injected with rHuPH20 results in a higher Cmax and earlier Tmax than when injected with carrier controls (page 437, right column, paragraph 3). Frost teaches that driving the pharmacokinetic profile from a traditional subcutaneous absorption curve towards an intravenous-like bolus profile may be valuable when peak blood levels and time to onset are critical to achieve the desired clinical response (page 438, right column, 5.2 Modified pharmacokinetics following subcutaneous injection with rHuPH20).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the amount of rHuPH20 in the composition of claims 1-53 of ‘485, Bookbinder, and Stuart PGPub such that the composition would have had an effective pharmacokinetic profile when administered subcutaneously. The person of ordinary skill in the art would have had a reasonable expectation of success based on the teaching of Frost, which suggested that rHuPH20 in combination with molecules up to several hundred nanometers in diameter confers favorable pharmacokinetics.
Regarding the amino acids, claims 1-53 of ‘485 do not recite that the composition further comprises one or more amino acid selected from methionine and histidine. However, Stuart PGPub teaches that administering a telomerase inhibitor in an aqueous solution with dissolution enhancers including amino acids ([0136]).
Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27). The concentration of histidine in the buffer is also 50 mM based on the 1:1 stoichiometry of histidine to hydrochloride. The adjusted pH of the buffered formulations is 6.0 (paragraph 115, line 30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to buffer the formulation of claims 1-53 of ‘485 modified by Bookbinder, Stuart PGPub, and Frost using the histidine hydrochloride buffer taught by Soane. One of ordinary skill would have been motivated to use a slightly acidic buffer system (such as pH 6.0) based on the activity of the hyaluronidase enzyme, which has an optimal pH at acidic to neutral conditions (Bookbinder column 25, lines 57-61).
Pertaining to claims 4 and 7-8, Bookbinder teaches truncation of the hydrophobic C-terminus of recombinant PH20 enzyme (column 86, Example 4, lines 7 and 18-20). Bookbinder teaches that the truncation may occur at residues P478, Q479, 1480, F481, Y482 (column 87, lines 14-15), N483 (column 86, line 64).Thus, Bookbinder teaches a fragment of the PH20 enzyme. One of ordinary skill in the art would have been motivated before the effective filing date of the claimed invention to use the truncated recombinant PH20 enzyme taught by Bookbinder in the combination of hyaluronidase enzyme (Bookbinder) and telomerase inhibitor (Stuart) discussed above in order to improve the solubility of the combination by removing the hydrophobic tail of hyaluronidase enzyme, as taught by Bookbinder.
Pertaining to claims 5-6 and 9, Bookbinder claim 1 recites “a hyaluronidase glycoprotein that consists of the sequence of amino acids set forth as amino acids 1-477, 36-477, 1-478, 36-478, 1-479, 36-479, 1-480, 36-480, 1-481, 36-481, 1-482, 36-482, 1-483 or 36-483 of 40 SEQ ID NO: 1,” wherein SEQ ID NO: 1 is 100% identical to the instant SEQ ID NO: 1, which represents the amino acid sequence of PH20. Thus, Bookbinder teaches N-terminal truncations of PH20 with a cleavage position before amino acid residue L36 and specifically teaches the PH20 fragment of 36-482. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the N-terminal truncations of PH20 taught by Bookbinder in the combination of Stuart and Bookbinder. One of ordinary skill would have recognized that the N-terminal leader sequence would not have been required for the enzymatic activity of the PH20 enzyme because the leader sequence would have been removed during cellular production prior to purification, as taught by Bookbinder (Example 9, Purification of sHASEGP, column 93, lines 4-6).
Pertaining to claims 12-13, Bookbinder teaches an embodiment in which a hyaluronidase domain of a sHASEGP polypeptide, or a catalytically active portion thereof, does not include the entire sequence of amino acids set forth in SEQ ID NO: 1 but is at least 90% or 95% identical to SEQ ID NO: 1 (column 6, lines 25-29), wherein SEQ ID NO: 1 of Bookbinder is identical to the instant SEQ ID NO: 1 (the amino acid sequence of wild-type PH20).
Regarding claim 14, Bookbinder teaches unit dosage forms of a hyaluronidase enzyme, such as 1 to 5,000 Units of the enzyme in a small volume (column 59, lines 31-33) that are suitable for administration to a human (column 59, lines 9-12). 1 to 5,000 Units of a hyaluronidase enzyme overlaps with 100 U to 50,000 U. Bookbinder also teaches that the unit dosage (1 to 5,000 units of the enzyme) can be prepackaged in a syringe for use, such as after viscoelastic injection (column 59, lines 34-35), which is a form of subcutaneous injection. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine a unit dosage of a hyaluronidase enzyme at a known and tolerated dosage acceptable for subcutaneous administration in a human with the telomerase inhibitor of Stuart in order to facilitate diffusion of the telomerase inhibitor, as discussed above. One of ordinary skill would have had a reasonable expectation of success given that the dosage of hyaluronidase enzyme taught by Bookbinder was formulated for subcutaneous administration.
Pertaining to claim 15, claim 22 of ‘485 recites that the telomerase inhibitor is administered with a pharmaceutically acceptable excipient.
Regarding claims 16-17, claims 1-53 of ‘485 do not recite that the composition further comprises one or more saccharides (claim 16) in an amount from 10 mM to 500 mM (claim 17).
Stuart PGPub teaches that administering a telomerase inhibitor in an aqueous solution with dissolution enhancers including 10% dextrose (a saccharide).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the composition of claims 1-53 of ‘485 and Bookbinder by including the dissolution enhancers taught by Stuart PGPub. The person of ordinary skill in the art would have been motivated to formulate the composition for injection prior to administration. The person of ordinary skill in the art would have had a reasonable expectation of success given that Stuart PGPub’s formulation was intended for a telomerase inhibitor.
A 10% dextrose solution is approximately 555 mM of saccharide, which is slightly above the claimed range of 10 mM to 500 mM. Therefore, a prima facie case of obviousness exists. See MPEP 2144.05.
Regarding instant claim 20, Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27). The concentration of histidine in the buffer is also 50 mM based on the 1:1 stoichiometry of histidine to hydrochloride. 50 mM is within the claimed range of 1 mM to 100 mM.
Pertaining to claim 21, claims 1-53 of ‘485 do not recite that the composition for administration further comprises a buffer.
Stuart PGPub teaches that the telomerase inhibitor is administered with a buffer ([0138]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the composition of claims 1-53 of ‘485 and Bookbinder by including a buffer the composition. The person of ordinary skill in the art would have been motivated based on the teaching of Stuart PGPub and would have had a reasonable expectation of success given that Stuart PGPub’s teaching was applicable to a telomerase inhibitor.
Pertaining to claims 22-23, claims 1-53 of ‘485 do not recite that the buffer is present in an amount sufficient to maintain the composition at a pH from 3.0 to 9.0 (claim 22) or that the buffer is present in the composition in an amount of from 1 to 100 mM (claim 23).
Bookbinder teaches that sHASEGP glycoproteins (hyaluronidase enzymes) are neutral active in vitro at pH between 5 and 8 under conditions of salt less than 150 mM and buffering strength less than 50 mM (column 25, lines 57-61). A buffering strength less than 50 mM overlaps with the claimed range of 1 to 100 mM. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to formulate a composition comprising both sHASEGP and a telomerase inhibitor at pH 5 to 8 in order to maintain the activity of the hyaluronidase enzyme. pH 5 to 8 overlaps with the claimed range of pH 3.0 to 9.0.
Regarding claim 30, claim 26 of ‘485 recites an effective amount of a telomerase inhibitor of 9.5 mg/kg to 11.7 mg/kg. The upper bound of this range is less than the instantly claimed range of about 17.0 mg/kg to 20.0 mg/kg.
Stuart PGPub also teaches that the telomerase inhibitor compounds are effective over a wide dosage range and that the amount of telomerase inhibitor compounds administered will be determined by a physician based on the chosen route of administration and other factors (age, weight, patient response, symptom severity). See [0085].
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the dosage of imetelstat per body weight in composition of claims 1-53 of ‘485 modified by Bookbinder, Stuart PGPub, and Frost based on the variables taught by Stuart PGPub and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
Regarding claim 31, claims 1-53 of ‘485 do not recite that the composition comprises about 1500 mg to about 1600 mg imetelstat.
Stuart PGPub teaches a method of treating myelofibrosis by administering imetelstat (see Stuart PGPub claims 9-10 and 30). In [0142], Stuart PGPub teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg. Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart PGPub teaches that the telomerase inhibitor may be administered in a range of dosages from 78 mg to 1014 mg (women) or from 91 mg to 1183 mg (men). Stuart PGPub’s upper bound for men is less than the instantly claimed range of about 1500 mg to about 1600 mg.
Stuart PGPub also teaches that telomerase inhibitor compounds are effective over a wide dosage range and are generally administered in a therapeutically effective amount (Stuart PGPub, [0085]). Stuart PGPub teaches: “It will be understood, however, that the amount of the telomerase inhibitor compounds actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms and the like” (Stuart PGPub, [0085]).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the composition in the method of claims 1-53 of ‘485 modified by Bookbinder, Stuart PGPub, and Frost based on the variables taught by Stuart PGPub and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
Regarding claim 32, claims 1-53 of ‘485 do not recite that the composition is lyophilized.
In [0081]-[0082], Stuart PGPub teaches that the active ingredient (telomerase inhibitor) may be lyophilized. Similarly, Bookbinder teaches that sHASEGP (a hyaluronidase enzyme) may be prepared as a lyophilized powder (Bookbinder, column 65, lines 31-32). Since both the telomerase inhibitor and the hyaluronidase enzyme may be prepared in lyophilized forms, it would have been obvious to one of ordinary skill to formulate a composition comprising both components in lyophilized form.
Regarding claim 138, claims 1-53 of ‘485 do not recite that the telomerase inhibitor dosage is about 1500 mg to 2500 mg.
Stuart PGPub teaches that telomerase inhibitor compounds are effective over a wide dosage range and are generally administered in a therapeutically effective amount (Stuart PGPub, [0085]). Stuart PGPub teaches: “It will be understood, however, that the amount of the telomerase inhibitor compounds actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms and the like” (Stuart PGPub, [0085]). Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of imetelstat in the composition of claims 1-53 of ‘485 modified by Bookbinder, Stuart PGPub, and Frost based on the variables taught by Stuart PGPub and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
Claim 10 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-53 of U.S. Patent No. 9,375,485 (‘485) in view of Bookbinder, Stuart PGPub, Frost, and Soane and as evidenced by Hanczyc and Centers for Disease Control, as applied to claims 1, 4-9, 12-17, 20-23, 30-32, and 138 above, further in view of Pecceu et al. (Genes Vol. 97, 1991, pp. 23-258).
See discussion of claims 1-53 of ‘485, Bookbinder, Stuart PGPub, Frost, and Soane above, which is incorporated into this rejection as well.
Bookbinder teaches enhanced mammalian expression systems using signal leaders capable of efficient secretion of sHASEGP (column 5, lines 51-53).
However, claims 1-53 of ‘485 do not recite and Bookbinder and Stuart PGPub do not teach that N-terminus of the PH20 fragment comprises a human growth hormone-derived signal peptide.
Pecceu teaches that human interleukin 1β fused to the human growth hormone signal peptide is secreted by Chinese hamster ovary cells (Title). The sequence of the human growth hormone signal peptide is given in Figure 1B and is identical to SEQ ID NO: 3 of the instant application. Fig. 2 demonstrates the signal peptide nucleotide sequence is fused to the N-terminus of the gene.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to further modify the PH20 enzyme fragment in the composition of claims 1-53 of ‘485 modified by Bookbinder, Stuart PGPub, and Frost such that the enzyme could be produced in a mammalian expression system. One skilled in the art would have recognized that the secretion of the PH20 enzyme fragment would have required a signal peptide recognized by the expression system. One of ordinary skill would have been motivated to use the human growth factor-derived signal peptide taught by Pecceu because of its demonstrated success in recombinant protein expression by Chinese hamster ovary cells.
Claims 70 and 102 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-53 of U.S. Patent No. 9,375,485 (‘485) in view of Bookbinder, Stuart PGPub, and Soane and as evidenced by Hanczyc and Centers for Disease Control.
See discussion of claims 1-53 of ‘485, Bookbinder and Stuart PGPub above, which is incorporated into this rejection as well.
Claims 1-53 of ‘485 do not recite and Bookbinder and Stuart PGPub do not teach that the composition further comprises methionine or histidine.
Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27). The concentration of histidine in the buffer is also 50 mM based on the 1:1 stoichiometry of histidine to hydrochloride. The adjusted pH of the buffered formulations is 6.0 (paragraph 115, line 30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to buffer the formulation of claims 1-53 of ‘485 modified by Bookbinder, Stuart PGPub, and Frost using the histidine hydrochloride buffer taught by Soane. One of ordinary skill would have been motivated to use a slightly acidic buffer system (such as pH 6.0) based on the activity of the hyaluronidase enzyme, which has an optimal pH at acidic to neutral conditions (Bookbinder column 25, lines 57-61).
Pertaining to claim 70, claims 1-53 of ‘485 do not recite that the composition is in unit dosage form.
Stuart PGPub teaches that a telomerase inhibitor composition may be formulated in a unit dosage form ([0081] and [0084]). Bookbinder teaches that sHASEGP polypeptides (human hyaluronidase enzymes) may be formulated in unit dosage forms (column 58, lines 59 and 67 and column 59, line 1). It would have been obvious to formulate the composition of claims 1-53 of ‘485 modified by Bookbinder and Stuart PGPub in unit dosage form comprising telomerase inhibitor imetelstat and an effective amount of the hyaluronidase enzyme rHuPH20 to enhance the systemic distribution of imetelstat. One of ordinary skill in the art would have recognized the benefit of formulating the composition in a unit dosage form for ease of administration to the subject.
Regarding the amount of telomerase inhibitor in the composition in unit dosage form, Stuart PGPub teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg ([0142]). Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart PGPub teaches that the telomerase inhibitor may be administered in a range of dosages from 78 mg to 1014 mg (women) or from 91 mg to 1183 mg (men). The upper bound of the range for men is less than the instantly claimed range of about 1500 mg to about 3000 mg.
Stuart PGPub also teaches that the telomerase inhibitor compounds are effective over a wide dosage range and that the amount of telomerase inhibitor compounds administered will be determined by a physician based on the chosen route of administration and other factors (age, weight, patient response, symptom severity). See [0085]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of imetelstat in the composition in unit dosage form as suggested by Stuart PGPub in the method of claims 1-53 of ‘485 modified by Bookbinder and Stuart PGPub. The person of ordinary skill in the art would have had a reasonable expectation of success in optimizing the dosage of imetelstat for subcutaneous administration with hyaluronidase.
Regarding claim 102, claims 1-53 of ‘485 do not recite that the composition is in a kit.
It would have been obvious to formulate the composition of claims 1-53 of ‘485 modified by Bookbinder and Stuart PGPub in a kit comprising telomerase inhibitor imetelstat and an effective amount of the hyaluronidase enzyme rHuPH20 to enhance the systemic distribution of imetelstat. One of ordinary skill in the art would have recognized the benefit of formulating the composition in a kit for the ease of retail to the customer (e.g. a medical clinic).
Regarding the amount of telomerase inhibitor in the composition in the kit, Stuart PGPub teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg ([0142]). Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart PGPub teaches that the telomerase inhibitor may be administered in a range of dosages from 78 mg to 1014 mg (women) or from 91 mg to 1183 mg (men). The upper bound of the range for men is less than the instantly claimed range of about 1500 mg to about 3000 mg.
Stuart PGPub also teaches that the telomerase inhibitor compounds are effective over a wide dosage range and that the amount of telomerase inhibitor compounds administered will be determined by a physician based on the chosen route of administration and other factors (age, weight, patient response, symptom severity). See [0085]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of imetelstat in the composition in a kit as suggested by Stuart PGPub in the method of claims 1-53 of ‘485 modified by Bookbinder and Stuart PGPub. The person of ordinary skill in the art would have had a reasonable expectation of success in optimizing the dosage of imetelstat for subcutaneous administration with hyaluronidase.
Claims 1, 4-9, 12-17, 20-23, 30-32, and 138 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 7,989,428 (‘428) in view of Bookbinder et al. (US 7,767,429 B2), Stuart et al. (US 9,375,485 B2), Frost et al. (Expert opinion on drug delivery 4.4 (2007): 427-440; cited in the Non-Final Action mailed on 4/24/2024) and Soane et al. (WO 2020/112855 A1; IDS filed 9/8/2022) and as evidenced by Hanczyc et al. (Langmuir, 2012, Vol. 28, pp. 6662−6669), by Centers for Disease Control (2021, website; cited in the Non-Final Action mailed on 12/30/2022) and by ClinicalTrials.gov (2021, website; cited in the Non-Final Action mailed on 12/30/2022).
Claim 1 of ‘428 is drawn to a method for inhibiting the proliferation of cancer cells, comprising exposing the cells to gemcitabine and exposing cells to a telomerase inhibitor consisting of an oligonucleotide 10-20 bases in length which is characterized by: (i) N3' ➔ P5' thiophosphoramidate linkages; (ii) having the sequence identified as SEQ ID NO: 12; (iii) a palmitoyl (Cl 6) moiety linked to the 5' terminus of the oligonucleotide via a glycerol or aminoglycerol linker.”
Claim 2 of ‘428 recites that the oligonucleotide is the compound designed as GRN163L.
Claim 3 of ‘428 limits the step of exposing the cells to intravenous infusion to achieve blood concentration of the inhibitor of between 1 nM and 100 µM.
Claim 4 of ‘428 requires that both gemcitabine and the telomerase inhibitor are administered in an effective amount, when administered alone, to inhibit the proliferation of cancer cells.
Clam 5 of ‘428 limits the subject of administration.
The telomerase inhibitor GRN163L (claim 2 of ‘428) is imetelstat, as evidenced by ClinicalTrials.gov (see Study Design, Official Title on page 3).
Therefore, claim 2 of ‘428 requires a composition comprising imetelstat in order to perform the method.
Claims 1-5 of ‘428 do not recite that the composition further comprises an effective amount of rHuPH20 or that the composition comprises about 1500 mg to about 3000 mg imetelstat in a unit dosage.
Bookbinder teaches human soluble PH20 hyaluronidase glycoproteins or sHASEGPs (column 3, lines 51-54). Bookbinder teaches rHuPH20, which is a recombinant human hyaluronidase enzyme, in Example 14 (line 15 of column 97). Thus, Bookbinder’s sHASEGPs are soluble recombinant forms of human hyaluronidase PH20 (rHuPH20). Bookbinder teaches that subcutaneous administration of molecules in the presence of sHASEGPs facilitates their rapid systemic distribution (column 8, lines 30-33). Bookbinder teaches that sHASEGPs open channels in the interstitial space through degradation of glycosaminoglycans (column 8, lines 2-5) and that these channels facilitate the diffusion of small molecules, proteins, and nucleic acids less than 500 nm in size (column 8, lines 6-10). Bookbinder teaches further that temporary removal of glycosaminoglycans enhances the delivery of drugs into interstitial spaces, which facilitates diffusion of therapeutic molecules and proteins (column 8, lines 26-30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the imetelstat of claim 2 of ‘428 with the rHuPH20of Bookbinder in an effective amount to enhance systemic distribution of the telomerase inhibitor for the treatment of cancer. One of ordinary skill in the art would have had a reasonable expectation of success given the teaching of Bookbinder that sHASEGPs (a species of hyaluronidase enzyme) facilitate the diffusion of many forms of therapeutic molecules and proteins, including small molecules, proteins, and nucleic acids, as long as they are less than 500 nm in size. Because the telomerase inhibitor of claims 1-5 of ‘428 was an oligonucleotide comprising only 10-20 nucleotides in length (claim 1 of ‘428) and lipid moiety up to 16 carbons in length (claim 1 of ‘428), it would have been obvious to one of ordinary skill that the oligonucleotide (telomerase inhibitor) of claims 1-5 of ‘428 is less than the 500 nm size limit taught by Bookbinder, as evidenced by Hanczyc (see Abstract of Hanczyc: an oligonucleotide less than 60 bases is less than 20.4 nm in size).
Regarding the amount of imetelstat, Stuart teaches the telomerase inhibitor is imetelstat (lines 32-34 of column 4). Stuart teaches that a telomerase inhibitor composition may be formulated in a unit dosage form (column 22, lines 48-49 and column 23, lines 19-20). In lines 34-59 of column 34, Stuart teaches that a telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg. Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 78 mg to 1014 mg (women) or from 91 mg to 1183 mg (men). The upper bound of Stuart’s range for men is less than the instantly claimed range of 1500 mg to 3000 mg.
Stuart also teaches that the telomerase inhibitor compounds are effective over a wide dosage range and that the amount of telomerase inhibitor compounds administered will be determined by a physician based on the chosen route of administration and other factors (age, weight, patient response, symptom severity). See lines 32-41 of column 23.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the telomerase inhibitor dosage in the composition of claims 1-5 of ‘428 modified by Bookbinder. The person of ordinary skill in the art would have been motivated to apply Stuart’s teachings and had a reasonable expectation of success because Stuart taught a method of cancer treatment using the same telomerase inhibitor as claims 1-5 of ‘428.
Claims 1-5 of ‘428 do not recite and Bookbinder and Stuart do not teach that the composition provides a therapeutically effective pharmacokinetic profile for the telomerase inhibitor when co-formulated with the recombinant human hyaluronidase enzyme.
Frost teaches that recombinant human hyaluronidase (rHuPH20) enables subcutaneous drug and fluid administration (Title). Specifically, Frost teaches that molecules up to several hundred nanometers in diameter are readily dispersed by co-administration with rHuPH20 and the pharmacokinetic profile of molecules co-injected with rHuPH20 results in a higher Cmax and earlier Tmax than when injected with carrier controls (page 437, right column, paragraph 3). Frost teaches that driving the pharmacokinetic profile from a traditional subcutaneous absorption curve towards an intravenous-like bolus profile may be valuable when peak blood levels and time to onset are critical to achieve the desired clinical response (page 438, right column, 5.2 Modified pharmacokinetics following subcutaneous injection with rHuPH20)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the amount of rHuPH20 in the composition of claims 1-5 of ‘428 modified by Bookbinder and Stuart such that the composition would have had an effective pharmacokinetic profile when administered subcutaneously. The person of ordinary skill in the art would have had a reasonable expectation of success based on the teaching of Frost, which suggested that rHuPH20 in combination with molecules up to several hundred nanometers in diameter confers favorable pharmacokinetics.
Claims 1-5 of ‘428 do not recite and Bookbinder and Stuart do not teach that the composition further comprises methionine or histidine.
Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27). The concentration of histidine in the buffer is also 50 mM based on the 1:1 stoichiometry of histidine to hydrochloride. The adjusted pH of the buffered formulations is 6.0 (paragraph 115, line 30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to buffer the formulation of claims 1-5 of ‘428 modified by Bookbinder, Stuart, and Frost using the histidine hydrochloride buffer taught by Soane. One of ordinary skill would have been motivated to use a slightly acidic buffer system (such as pH 6.0) based on the activity of the hyaluronidase enzyme, which has an optimal pH at acidic to neutral conditions (Bookbinder column 25, lines 57-61).
Pertaining to claims 4 and 7-8, Bookbinder teaches truncation of the hydrophobic C-terminus of recombinant PH20 enzyme (column 86, Example 4, lines 7 and 18-20). Bookbinder teaches that the truncation may occur at residues P478, Q479, 1480, F481, Y482 (column 87, lines 14-15), N483 (column 86, line 64).Thus, Bookbinder teaches a fragment of the PH20 enzyme. One of ordinary skill in the art would have been motivated before the effective filing date of the claimed invention to use the truncated recombinant PH20 enzyme taught by Bookbinder in the combination of hyaluronidase enzyme (Bookbinder) and telomerase inhibitor (claims 1-5 of ‘428) discussed above in order to improve the solubility of the combination by removing the hydrophobic tail of hyaluronidase enzyme, as taught by Bookbinder.
Pertaining to claims 5-6 and 9, Bookbinder claim 1 recites “a hyaluronidase glycoprotein that consists of the sequence of amino acids set forth as amino acids 1-477, 36-477, 1-478, 36-478, 1-479, 36-479, 1-480, 36-480, 1-481, 36-481, 1-482, 36-482, 1-483 or 36-483 of 40 SEQ ID NO: 1,” wherein SEQ ID NO: 1 is 100% identical to the instant SEQ ID NO: 1, which represents the amino acid sequence of PH20. Thus, Bookbinder teaches N-terminal truncations of PH20 with a cleavage position before amino acid residue L36 and specifically teaches the PH20 fragment of 36-482. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the N-terminal truncations of PH20 taught by Bookbinder in the combination of claims 1-5 of ‘428 and Bookbinder. One of ordinary skill would have recognized that the N-terminal leader sequence would not have been required for the enzymatic activity of the PH20 enzyme because the leader sequence would have been removed during cellular production prior to purification, as taught by Bookbinder (Example 9, Purification of sHASEGP, column 93, lines 4-6).
Pertaining to claims 12-13, Bookbinder teaches an embodiment in which a hyaluronidase domain of a sHASEGP polypeptide, or a catalytically active portion thereof, does not include the entire sequence of amino acids set forth in SEQ ID NO: 1 but is at least 90% or 95% identical to SEQ ID NO: 1 (column 6, lines 25-29), wherein SEQ ID NO: 1 of Bookbinder is identical to the instant SEQ ID NO: 1 (the amino acid sequence of wild-type PH20).
Regarding claim 14, Bookbinder teaches unit dosage forms of a hyaluronidase enzyme, such as 1 to 5,000 Units of the enzyme in a small volume (column 59, lines 31-33) that are suitable for administration to a human (column 59, lines 9-12). 1 to 5,000 Units of a hyaluronidase enzyme overlaps with 100 U to 50,000 U. Bookbinder also teaches that the unit dosage (1 to 5,000 units of the enzyme) can be prepackaged in a syringe for use, such as after viscoelastic injection (column 59, lines 34-35), which is a form of subcutaneous injection. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine a unit dosage of a hyaluronidase enzyme at a known and tolerated dosage acceptable for subcutaneous administration in a human with the telomerase inhibitor of claims 1-5 of ‘428 modified by Bookbinder, Stuart, and Frost in order to facilitate diffusion of the telomerase inhibitor. One of ordinary skill in the art would have had a reasonable expectation of success given that the dosage of hyaluronidase enzyme taught by Bookbinder was formulated for subcutaneous administration.
Pertaining to claim 15, claims 1-5 of ‘428 do not recite that the telomerase inhibitor is administered with a pharmaceutically acceptable excipient.
Stuart teaches that the telomerase inhibitor imetelstat is administered with a pharmaceutically acceptable excipient (column 4, lines 32-36). Stuart teaches administering imetelstat for the treatment of cancer (Stuart claims 21 and 6; Stuart column 3, lines 5-7)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to further modify the composition of claims 1-5 of ‘428 and Bookbinder per the teaching of Stuart to incorporate a pharmaceutically acceptable excipient. The person of ordinary skill in the art would have been motivated to apply the teachings of Stuart and had a reasonable expectation of success because Stuart also taught a method of administering the same telomerase inhibitor (imetelstat) for the treatment of cancer.
Pertaining to claims 16 -17, claims 1-5 of ‘428 do not recite that the composition further comprises one or more saccharides in the composition in an amount from 10 mM to 500 mM or that the composition further comprises one or more amino acids.
Stuart teaches that the telomerase inhibitor is administered as an aqueous solution with dissolution enhancers including 10% dextrose (a saccharide). A 10% dextrose solution is approximately 555 mM of saccharide, which is slightly above the claimed range of 10 mM to 500 mM. Therefore, a prima facie case of obviousness exists. See MPEP 2144.05. Stuart’s formulation is suitable for both intravenous as well as subcutaneous injection (see Stuart claim 23).
Pertaining to claim 21, claims 1-5 of ‘428 do not recite that the composition further comprises a buffer.
Stuart teaches that the telomerase inhibitor is administered with a buffer (column 33, lines 7-8).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to apply Stuart’s teachings regarding incorporating polysaccharides and a buffer to the composition of claims 1-5 of ‘428 modified by Bookbinder, Stuart, and Frost. The person of ordinary skill in the art would have been motivated to apply Stuart’s teachings and had a reasonable expectation of success because Stuart taught a formulation comprising the same telomerase inhibitor (imetelstat) in a composition that was suitable for both intravenous and subcutaneous injection.
Pertaining to claim 20, Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27). The concentration of histidine in the buffer is also 50 mM based on the 1:1 stoichiometry of histidine to hydrochloride. 50 mM is within the claimed range of from 1 mM to 100 mM.
Pertaining to claims 22-23, Bookbinder teaches that sHASEGP glycoproteins (hyaluronidase enzymes) are neutral active in vitro at pH between 5 and 8 under conditions of salt less than 150 mM and buffering strength less than 50 mM (column 25, lines 57-61). A buffering strength less than 50 mM overlaps with the claimed range of 1 to 100 mM. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to formulate a composition comprising both sHASEGP and a telomerase inhibitor at acidic pH 5 to 8 in order to maintain the activity of the hyaluronidase enzyme. pH 5 to 8 overlaps with the claimed range of pH 3.0 to 9.0.
Regarding claim 30, claims 1-5 of ‘428 do not recite that the telomerase inhibitor dosage per body weight is about 17.0 mg/kg to 20.0 mg/kg.
Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg (lines 34-59 of column 34).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to apply Stuart’s teachings regarding dosage to the composition of claims 1-5 of ‘428 modified by Bookbinder, Stuart, and Frost. The upper bound of Stuart’s range is a value less than the lower bound of the instantly claimed range of about 17.0 mg/kg to 20.0 mg/kg.
Stuart also teaches that the telomerase inhibitor compounds are effective over a wide dosage range and that the amount of telomerase inhibitor compounds administered will be determined by a physician based on the chosen route of administration and other factors (age, weight, patient response, symptom severity). See lines 32-41 of column 23.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of telomerase inhibitor dosage per body weight in the method of claims 1-5 of ‘428 modified by Bookbinder, Stuart and Frost per the parameters taught by Stuart. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the dosage per body weight.
Regarding claim 31, in lines 34-59 of column 34, Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg. Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 78 mg to 1014 mg (women) or from 91 mg to 1183 mg (men). The upper bound of Stuart’s range for men is less than the instantly claimed range of 1500 mg to 1600 mg.
Stuart also teaches that telomerase inhibitor compounds are effective over a wide dosage range and are generally administered in a therapeutically effective amount (Stuart, lines 32-34 of column 23). Stuart teaches: “It will be understood, however, that the amount of the telomerase inhibitor compounds actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms and the like” (Stuart, lines 32-41 of column 23).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the composition of claims 1-5 of ‘428 modified by Bookbinder, Stuart, and Frost based on the variables taught by Stuart and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
Regarding claim 32, claims 1-5 of ‘428 do not recite that the composition is lyophilized.
In lines 45-46 and 65-66 of column 22, Stuart teaches that the active ingredient (the telomerase inhibitor imetelstat) may be lyophilized (claim 32). Similarly, Bookbinder teaches that sHASEGP (a hyaluronidase enzyme) may be prepared as a lyophilized powder (Bookbinder, column 65, lines 31-32).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to apply Stuart’s teachings regarding lyophilization to the composition of claims 1-5 of ‘428 modified by Bookbinder, Stuart, and Frost. The person of ordinary skill in the art would have been motivated to apply Stuart’s teachings and had a reasonable expectation of success because Stuart taught a formulation comprising the same telomerase inhibitor (imetelstat). Since both the telomerase inhibitor and the hyaluronidase enzyme may be prepared in lyophilized forms, it would have been obvious to one of ordinary skill in the art to formulate a composition comprising both components in lyophilized form.
Regarding claim 138, claims 1-5 of ‘428 do not recite that the telomerase inhibitor dosage is about 1500 mg to 2500 mg.
Stuart teaches that telomerase inhibitor compounds are effective over a wide dosage range and are generally administered in a therapeutically effective amount (Stuart, lines 32-34 of column 23). Stuart teaches: “It will be understood, however, that the amount of the telomerase inhibitor compounds actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms and the like” (Stuart, lines 32-41 of column 23). Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of imetelstat in the composition of claims 1-5 of ‘428 modified by Bookbinder, Stuart, and Frost based on the variables taught by Stuart and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
Claim 10 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 7,989,428 (‘428) in view of Bookbinder, Stuart, Frost, and Soane and as evidenced by Hanczyc, Centers for Disease Control, and ClinicalTrials.gov, as applied to claims 1, 4-9, 12-17, 20-23, 30-32, and 138 above, further in view of Pecceu et al. (Genes Vol. 97, 1991, pp. 23-258).
See discussion of claims 1-5 of ‘428, Bookbinder, Stuart, Frost, and Soane above, which is incorporated into this rejection as well.
Bookbinder teaches enhanced mammalian expression systems using signal leaders capable of efficient secretion of sHASEGP (column 5, lines 51-53).
Claims 1-5 of ‘428 do not recite and Bookbinder, Stuart, and Frost do not teach that N-terminus of the PH20 fragment comprises a human growth hormone-derived signal peptide.
Pecceu teaches that human interleukin 1β fused to the human growth hormone signal peptide is secreted by Chinese hamster ovary cells (Title). The sequence of the human growth hormone signal peptide is given in Figure 1B and is identical to SEQ ID NO: 3 of the instant application. Fig. 2 demonstrates the signal peptide nucleotide sequence is fused to the N-terminus of the gene.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to further modify the PH20 enzyme fragment in the composition of claims 1-5 of ‘428 modified by Bookbinder, Stuart, and Frost such that the enzyme could be produced in a mammalian expression system. One skilled in the art would have recognized that the secretion of the PH20 enzyme fragment would have required a signal peptide recognized by the expression system. One of ordinary skill would have been motivated to use the human growth factor-derived signal peptide taught by Pecceu because of its demonstrated success in recombinant protein expression by Chinese hamster ovary cells.
Claims 70 and 102 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 7,989,428 (‘428) in view of Bookbinder, Stuart, and Soane and as evidenced by Hanczyc, Centers for Disease Control, and ClinicalTrials.gov.
See discussion of claims 1-5 of ‘428, Bookbinder and Stuart above, which is incorporated into this rejection as well.
Claims 1-5 of ‘428 do not recite and Bookbinder and Stuart do not teach that the composition further comprises methionine or histidine.
Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27). The concentration of histidine in the buffer is also 50 mM based on the 1:1 stoichiometry of histidine to hydrochloride. The adjusted pH of the buffered formulations is 6.0 (paragraph 115, line 30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to buffer the formulation of claims 1-5 of ‘428 modified by Bookbinder, Stuart, and Frost using the histidine hydrochloride buffer taught by Soane. One of ordinary skill would have been motivated to use a slightly acidic buffer system (such as pH 6.0) based on the activity of the hyaluronidase enzyme, which has an optimal pH at acidic to neutral conditions (Bookbinder column 25, lines 57-61).
Pertaining to claim 70, claims 1-5 of ‘428 do not recite that the composition is in unit dosage form.
Stuart teaches that a telomerase inhibitor composition may be formulated in a unit dosage form (column 22, lines 48-49 and column 23, lines 19-20). Bookbinder teaches that sHASEGP polypeptides (human hyaluronidase enzymes) may be formulated in unit dosage forms (column 58, lines 59 and 67 and column 59, line 1). It would have been obvious to formulate the composition of claims 1-5 of ‘428 modified by Stuart and Bookbinder in unit dosage form comprising telomerase inhibitor imetelstat and an effective amount of the hyaluronidase enzyme rHuPH20 to enhance the systemic distribution of imetelstat. One of ordinary skill in the art would have recognized the benefit of formulating the composition in a unit dosage form for ease of administration to the subject.
Regarding the amount of telomerase inhibitor in the composition in unit dosage form, Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg (lines 34-59 of column 34,). Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 78 mg to 1014 mg (women) or from 91 mg to 1183 mg (men). The upper bound of the range for men approaches the lower bound of the instantly claimed range of about 1500 mg to about 3000 mg.
Stuart also teaches that the telomerase inhibitor compounds are effective over a wide dosage range and that the amount of telomerase inhibitor compounds administered will be determined by a physician based on the chosen route of administration and other factors (age, weight, patient response, symptom severity). See lines 32-41 of column 23.
It would have been further obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of imetelstat in the unit dosage form in the method of claims 1-5 of ‘428 modified by Bookbinder per Stuart’s recommendation. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the imetelstat dosage.
Regarding claim 102, claims 1-5 of ‘428 do not recite that the composition is in a kit.
It would have been obvious to formulate the composition of claims 1-5 of ‘428 modified by Bookbinder and Stuart in a kit comprising telomerase inhibitor imetelstat and an effective amount of the hyaluronidase enzyme rHuPH20 to enhance the systemic distribution of imetelstat. One of ordinary skill in the art would have recognized the benefit of formulating the composition in a kit for the ease of retail to the customer (e.g. a medical clinic).
Regarding the amount of telomerase inhibitor in the composition in the kit, Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg (lines 34-59 of column 34,). Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 78 mg to 1014 mg (women) or from 91 mg to 1183 mg (men). The upper bound of the range for men is less than the lower bound of the instantly claimed range of about 1500 mg to about 3000 mg.
Stuart also teaches that the telomerase inhibitor compounds are effective over a wide dosage range and that the amount of telomerase inhibitor compounds administered will be determined by a physician based on the chosen route of administration and other factors (age, weight, patient response, symptom severity). See lines 32-41 of column 23.
It would have been further obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of imetelstat in the kit to perform the method of claims 1-5 of ‘428 modified by Bookbinder, per Stuart’s recommendation. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the imetelstat dosage in the kit.
Claims 1, 4-9, 12-17, 20-23, 31-32, and 138 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 7,998,938 (‘938) in view of Bookbinder et al. (US 7,767,429 B2), Stuart et al. (US 9,375,485 B2), Frost et al. (Expert opinion on drug delivery 4.4 (2007): 427-440; cited in the Non-Final Action mailed on 4/24/2024), and Soane and as evidenced by Hanczyc et al. (Langmuir, 2012, Vol. 28, pp. 6662−6669), by Centers for Disease Control (2021, website; cited in the Non-Final Action mailed on 12/30/2022), and by ClinicalTrials.gov (2012, website; cited in the Non-Final Action mailed on 12/30/2022).
Claim 1 of ‘938 is drawn to a method for inhibiting the proliferation of multiple myeloma cancer cells comprising exposing the cells to the proteasome inhibitor bortezomib and exposing the cells to a telomerase inhibitor, wherein the telomerase inhibitor includes an oligonucleotide which is characterized by: (i) N3' ➔ P5' thiophosphoramidate internucleoside linkages; (ii) having the sequence identified as SEQ ID NO: 12; and (iii) a palmitoyl (C16) moiety linked to the 5' terminus of the oligonucleotide via a glycerol or aminoglycerol linker;
Claim 2 of ‘938 limits the oligonucleotide to 10-20 bases in length.
Claim 3 of ‘938 limits the telomerase inhibitor to GRN163L. Claims 4-7 of ‘938 further limit the method of claim 1 of ‘938.
Claim 8 of ‘938 is drawn to a method for enhancing the anti-cancer treatment efficacy of the proteasome inhibitor bortezomib comprising administering an oligonucleotide telomerase inhibitor. Claims 9-13 of ‘938 further limit the method of claim 8 of ‘938.
Claims 14-16 of ‘938 are drawn to a kit comprising the proteasome inhibitor bortezomib and telomerase inhibitor.
The telomerase inhibitor GRN163L (claim 3 of ‘938) is imetelstat, as evidenced by ClinicalTrials.gov (see Study Design, Official Title on page 3).
Claims 1-16 of ‘938 do not recite that the composition further comprises an effective amount of rHuPH20.
Bookbinder teaches human soluble PH20 hyaluronidase glycoproteins or sHASEGPs (column 3, lines 51-54). Bookbinder teaches rHuPH20, which is a recombinant human hyaluronidase enzyme, in Example 14 (line 15 of column 97). Thus, Bookbinder’s sHASEGPs are soluble recombinant forms of human hyaluronidase PH20 (rHuPH20). Bookbinder teaches that subcutaneous administration of molecules in the presence of sHASEGPs facilitates their rapid systemic distribution (column 8, lines 30-33). Bookbinder teaches that sHASEGPs open channels in the interstitial space through degradation of glycosaminoglycans (column 8, lines 2-5) and that these channels facilitate the diffusion of small molecules, proteins, and nucleic acids less than 500 nm in size (column 8, lines 6-10). Bookbinder teaches further that temporary removal of glycosaminoglycans enhances the delivery of drugs into interstitial spaces, which facilitates diffusion of therapeutic molecules and proteins (column 8, lines 26-30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the telomerase inhibitor imetelstat of claims 1-16 of ‘938 with the hyaluronidase enzyme rHuPH20 of Bookbinder in an effective amount to enhance systemic distribution of the telomerase inhibitor for the treatment of cancer. One of ordinary skill in the art would have had a reasonable expectation of success given the teaching of Bookbinder that sHASEGPs (a species of hyaluronidase enzyme) facilitated the diffusion of many forms of therapeutic molecules and proteins, including small molecules, proteins, and nucleic acids, as long as they were less than 500 nm in size. Because the telomerase inhibitor of claims 1-16 of ‘938 was an oligonucleotide comprising only 10-20 nucleotides (claim 2 of ‘938) and lipid moiety up to 16 carbons in length (claim 1 of ‘938), it would have been obvious to one of ordinary skill that the oligonucleotide (telomerase inhibitor) of claims 1-16 of ‘938 was less than the 500 nm size limit taught by Bookbinder, as evidenced by Hanczyc (see Abstract of Hanczyc: an oligonucleotide less than 60 bases is less than 20.4 nm in size).
Claims 1-16 of 938 do not recite that the amount of imetelstat is about 1500 mg to about 3000 mg in a unit dosage form.
Stuart teaches that a telomerase inhibitor composition may be formulated in a unit dosage form (column 22, lines 48-49 and column 23, lines 19-20). In lines 34-59 of column 34, Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg. Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 78 mg to 1014 mg (women) or from 91 mg to 1183 mg (men). The upper bound of Stuart’s range for men from 91 mg to 1183 mg approaches the instantly claimed range of 1500 mg to 3000 mg.
Stuart also teaches that the telomerase inhibitor compounds are effective over a wide dosage range and that the amount of telomerase inhibitor compounds administered will be determined by a physician based on the chosen route of administration and other factors (age, weight, patient response, symptom severity). See lines 32-41 of column 23.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of imetelstat per Stuart’s recommendations in the composition of claims 1-16 of ‘938 modified by Bookbinder. The person of ordinary skill in the art would have been motivated to do so and had a reasonable expectation of success given that Stuart teaches the same telomerase inhibitor, which is also for the treatment of cancer.
Claims 1-16 of 938 do not recite and Stuart and Bookbinder do not teach that the composition provides a therapeutically effective pharmacokinetic profile for the telomerase inhibitor when co-formulated with the recombinant human hyaluronidase enzyme.
Frost teaches that recombinant human hyaluronidase (rHuPH20) enables subcutaneous drug and fluid administration (Title). Specifically, Frost teaches that molecules up to several hundred nanometers in diameter are readily dispersed by co-administration with rHuPH20 and the pharmacokinetic profile of molecules co-injected with rHuPH20 results in a higher Cmax and earlier Tmax than when injected with carrier controls (page 437, right column, paragraph 3). Frost teaches that driving the pharmacokinetic profile from a traditional subcutaneous absorption curve towards an intravenous-like bolus profile may be valuable when peak blood levels and time to onset are critical to achieve the desired clinical response (page 438, right column, 5.2 Modified pharmacokinetics following subcutaneous injection with rHuPH20)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the amount of rHuPH20 in the composition of claims 1-16 of 938, Bookbinder, and Stuart such that the composition would have had an effective pharmacokinetic profile when administered subcutaneously. The person of ordinary skill in the art would have had a reasonable expectation of success based on the teaching of Frost, which suggested that rHuPH20 in combination with molecules up to several hundred nanometers in diameter confers favorable pharmacokinetics.
Claims 1-16 of ‘938 do not recite and Bookbinder, Stuart, and Frost do not teach that that the composition further comprises methionine or histidine.
Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27). The concentration of histidine in the buffer is also 50 mM based on the 1:1 stoichiometry of histidine to hydrochloride. The adjusted pH of the buffered formulations is 6.0 (paragraph 115, line 30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to buffer the formulation of claims 1-16 of ‘938 modified by Bookbinder, Stuart, and Frost using the histidine hydrochloride buffer taught by Soane. One of ordinary skill would have been motivated to use a slightly acidic buffer system (such as pH 6.0) based on the activity of the hyaluronidase enzyme, which has an optimal pH at acidic to neutral conditions (Bookbinder column 25, lines 57-61).
Pertaining to claims 4 and 7-8, Bookbinder teaches truncation of the hydrophobic C-terminus of recombinant PH20 enzyme (column 86, Example 4, lines 7 and 18-20). Bookbinder teaches that the truncation may occur at residues P478, Q479, 1480, F481, Y482 (column 87, lines 14-15), N483 (column 86, line 64).Thus, Bookbinder teaches a fragment of the PH20 enzyme. One of ordinary skill in the art would have been motivated before the effective filing date of the claimed invention to use the truncated recombinant PH20 enzyme taught by Bookbinder in the combination of hyaluronidase enzyme (Bookbinder) and telomerase inhibitor (claims 1-16 of ‘938) discussed above in order to improve the solubility of the combination by removing the hydrophobic tail of hyaluronidase enzyme, as taught by Bookbinder.
Pertaining to claims 5-6 and 9, Bookbinder claim 1 recites “a hyaluronidase glycoprotein that consists of the sequence of amino acids set forth as amino acids 1-477, 36-477, 1-478, 36-478, 1-479, 36-479, 1-480, 36-480, 1-481, 36-481, 1-482, 36-482, 1-483 or 36-483 of 40 SEQ ID NO: 1,” wherein SEQ ID NO: 1 is 100% identical to the instant SEQ ID NO: 1, which represents the amino acid sequence of PH20. Thus, Bookbinder teaches N-terminal truncations of PH20 with a cleavage position before amino acid residue L36 and specifically teaches the PH20 fragment of 36-482. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the N-terminal truncations of PH20 taught by Bookbinder in the combination of claims 1-16 of ‘938 and Bookbinder. One of ordinary skill would have recognized that the N-terminal leader sequence would not have been required for the enzymatic activity of the PH20 enzyme because the leader sequence would have been removed during cellular production prior to purification, as taught by Bookbinder (Example 9, Purification of sHASEGP, column 93, lines 4-6).
Pertaining to claims 12-13, Bookbinder teaches an embodiment in which a hyaluronidase domain of a sHASEGP polypeptide, or a catalytically active portion thereof, does not include the entire sequence of amino acids set forth in SEQ ID NO: 1 but is at least 90% or 95% identical to SEQ ID NO: 1 (column 6, lines 25-29), wherein SEQ ID NO: 1 of Bookbinder is identical to the instant SEQ ID NO: 1 (the amino acid sequence of wild-type PH20).
Regarding claim 14, Bookbinder teaches unit dosage forms of a hyaluronidase enzyme, such as 1 to 5,000 Units of the enzyme in a small volume (column 59, lines 31-33) that are suitable for administration to a human (column 59, lines 9-12). 1 to 5,000 Units of a hyaluronidase enzyme overlaps with 100 U to 50,000 U. Bookbinder also teaches that the unit dosage (1 to 5,000 units of the enzyme) can be prepackaged in a syringe for use, such as after viscoelastic injection (column 59, lines 34-35), which is a form of subcutaneous injection. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine a unit dosage of a hyaluronidase enzyme at a known and tolerated dosage acceptable for subcutaneous administration in a human with the telomerase inhibitor of claims 1-16 of ‘938 in order to facilitate diffusion of the telomerase inhibitor, as discussed above. One of ordinary skill would have had a reasonable expectation of success given that the dosage of hyaluronidase enzyme taught by Bookbinder was formulated for subcutaneous administration.
Pertaining to claim 15, claims 1-16 of ‘938 do not recite that imetelstat is administered with a pharmaceutically acceptable excipient.
Stuart teaches that a telomerase inhibitor is administered for the treatment of cancer with a pharmaceutically acceptable excipient (column 3 lines 6-7, Stuart claim 1 and column 4, lines 34-36). Stuart teaches that the composition comprising the telomerase inhibitor may be administered subcutaneously or intravenously (Stuart claim 23).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the composition of claims 1-16 of ‘938 and Bookbinder to include a pharmaceutically acceptable excipient per the teachings of Stuart. The person of ordinary skill in the art would have been motivated to make this modification and had a reasonable expectation of success given that Stuart taught the administration of a telomerase inhibitor with the same structure as the telomerase inhibitor in claims 1-16 of ‘938 and the inhibitor was also administered to treat cancer (see Stuart claim 1).
Pertaining to claims 16 -17, claims 1-16 of ‘938 do not recite that the composition comprises 10 mM to 500 mM of saccharides.
Stuart teaches that the telomerase inhibitor is administered as an aqueous solution with dissolution enhancers including 10% dextrose (a saccharide). A 10% dextrose solution is approximately 555 mM of saccharide, which is slightly above the claimed range of 10 mM to 500 mM. Therefore, a prima facie case of obviousness exists. See MPEP 2144.05.
Pertaining to claim 21, Stuart teaches that the telomerase inhibitor is administered with a buffer (column 33, lines 7-8).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the composition of claims 1-16 of ‘938 and Bookbinder to include polysaccharides and a buffer per the teachings of Stuart. The person of ordinary skill in the art would have been motivated to make this modification and had a reasonable expectation of success given that Stuart taught the administration of a telomerase inhibitor with the same structure as the telomerase inhibitor in claims 1-16 of ‘938 and the inhibitor was also administered to treat cancer (see Stuart claim 1).
Pertaining to claim 20, Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27). The concentration of histidine in the buffer is also 50 mM based on the 1:1 stoichiometry of histidine to hydrochloride. 50 mM is within the claimed range of from 1 mM to 100 mM.
Pertaining to claims 22-23, Bookbinder teaches that sHASEGP glycoproteins (hyaluronidase enzymes) are neutral active in vitro at pH between 5 and 8 under conditions of salt less than 150 mM and buffering strength less than 50 mM (column 25, lines 57-61). A buffering strength less than 50 mM overlaps with the claimed range of 1 to 100 mM. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to formulate a composition comprising both sHASEGP and a telomerase inhibitor at acidic pH 5 to 8 in order to maintain the activity of the hyaluronidase enzyme. pH 5 to 8 overlaps with the claimed range of pH 3.0 to 9.0.
Regarding claim 30, claims 1-16 of ‘938 do not recite the dosage per body weight of imetelstat is about 17.0 mg/kg to about 20 mg/kg.
Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg (lines 34-59 of column 34). The upper bound of this range is a value less than the instantly claimed range. Stuart also teaches that the telomerase inhibitor compounds are effective over a wide dosage range and that the amount of telomerase inhibitor compounds administered will be determined by a physician based on the chosen route of administration and other factors (age, weight, patient response, symptom severity). See lines 32-41 of column 23.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the dosage per body weight of imetelstat per Stuart’s recommendations in the composition of claims 1-16 of ‘938 modified by Bookbinder, Stuart, and Frost. The person of ordinary skill in the art would have had a reasonable expectation of success in doing so.
Regarding claim 31, claims 1-16 of ‘938 do not recite the imetelstat dosage is about 1500 mg to about 1600 mg.
In lines 34-59 of column 34, Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg. Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 78 mg to 1014 mg (women) or from 91 mg to 1183 mg (men). The upper bound of Stuart’s range for men from 91 mg to 1183 mg is less than the instantly claimed range of 1500 mg to 1600 mg.
Stuart also teaches that telomerase inhibitor compounds are effective over a wide dosage range and are generally administered in a therapeutically effective amount (Stuart, lines 32-34 of column 23). Stuart teaches: “It will be understood, however, that the amount of the telomerase inhibitor compounds actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms and the like” (Stuart, lines 32-41 of column 23).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the composition of claims 1-16 of ‘938 modified by Bookbinder, Stuart, and Frost based on the variables taught by Stuart and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
Regarding claim 32, claims 1-16 of ‘938 do not recite and Bookbinder does not teach that the composition is lyophilized.
In lines 45-46 and 65-66 of column 22, Stuart teaches that the active ingredient (telomerase inhibitor) may be lyophilized. Similarly, Bookbinder teaches that sHASEGP (a hyaluronidase enzyme) may be prepared as a lyophilized powder (Bookbinder, column 65, lines 31-32). Since both the telomerase inhibitor and the hyaluronidase enzyme may be prepared in lyophilized forms, it would have been obvious to one of ordinary skill to formulate the composition comprising both components in lyophilized form.
Regarding claim 138, claims 1-16 of ‘938 do not recite that the telomerase inhibitor dosage is about 1500 mg to 2500 mg.
Stuart teaches that telomerase inhibitor compounds are effective over a wide dosage range and are generally administered in a therapeutically effective amount (Stuart, lines 32-34 of column 23). Stuart teaches: “It will be understood, however, that the amount of the telomerase inhibitor compounds actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms and the like” (Stuart, lines 32-41 of column 23). Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of imetelstat in the composition of claims 1-16 of ‘938 modified by Bookbinder, Stuart, and Frost based on the variables taught by Stuart and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
Claim 10 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 7,998,938 (‘938) in view of Bookbinder, Stuart, Frost, and Soane and as evidenced by Hanczyc, Centers for Disease Control, and ClinicalTrials.gov, as applied to claims 1, 4-9, 12-17, 20-23, 30-32, and 138 above, further in view of Pecceu et al. (Genes Vol. 97, 1991, pp. 23-258).
See discussion of claims 1-16 of ‘938, Bookbinder, Stuart, Frost, and Soane above, which is incorporated into this rejection as well.
Bookbinder teaches enhanced mammalian expression systems using signal leaders capable of efficient secretion of sHASEGP (column 5, lines 51-53).
Claims 1-16 of ‘938 do not recite that N-terminus of the PH20 fragment comprises a human growth hormone-derived signal peptide.
Pecceu teaches that human interleukin 1β fused to the human growth hormone signal peptide is secreted by Chinese hamster ovary cells (Title). The sequence of the human growth hormone signal peptide is given in Figure 1B and is identical to SEQ ID NO: 3 of the instant application. Fig. 2 demonstrates the signal peptide nucleotide sequence is fused to the N-terminus of the gene.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to further modify the PH20 enzyme fragment in the composition of claims 1-16 of ‘938 modified by Bookbinder, Stuart, and Frost such that the enzyme could be produced in a mammalian expression system. One skilled in the art would have recognized that the secretion of the PH20 enzyme fragment would have required a signal peptide recognized by the expression system. One of ordinary skill would have been motivated to use the human growth factor-derived signal peptide taught by Pecceu because of its demonstrated success in recombinant protein expression by Chinese hamster ovary cells.
Claims 70 and 102 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 7,998,938 (‘938) in view of Bookbinder et al. (US 7,767,429 B2), Stuart et al. (US 9,375,485 B2), and Soane and as evidenced by Hanczyc et al. (Langmuir, 2012, Vol. 28, pp. 6662−6669), Centers for Disease Control, and ClinicalTrials.gov.
See discussion of claims 1-16 of ‘938, Bookbinder, and Stuart above, which is incorporated into this rejection as well.
Claims 1-16 of ‘938 do not recite and Bookbinder, Stuart, and Frost do not teach that that the composition further comprises methionine or histidine.
Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27). The concentration of histidine in the buffer is also 50 mM based on the 1:1 stoichiometry of histidine to hydrochloride. The adjusted pH of the buffered formulations is 6.0 (paragraph 115, line 30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to buffer the formulation of claims 1-16 of ‘938 modified by Bookbinder, Stuart, and Frost using the histidine hydrochloride buffer taught by Soane. One of ordinary skill would have been motivated to use a slightly acidic buffer system (such as pH 6.0) based on the activity of the hyaluronidase enzyme, which has an optimal pH at acidic to neutral conditions (Bookbinder column 25, lines 57-61).
Pertaining to claim 70, claims 1-16 of ‘938 do not recite that the composition is in unit dosage form.
Stuart teaches that a telomerase inhibitor composition may be formulated in a unit dosage form (column 22, lines 48-49 and column 23, lines 19-20). Bookbinder teaches that sHASEGP polypeptides (human hyaluronidase enzymes) may be formulated in unit dosage forms (column 58, lines 59 and 67 and column 59, line 1). It would have been obvious to formulate the composition of claims 1-16 of ‘938 modified by Bookbinder and Stuart in unit dosage form comprising telomerase inhibitor imetelstat and an effective amount of the hyaluronidase enzyme rHuPH20 to enhance the systemic distribution of imetelstat. One of ordinary skill in the art would have recognized the benefit of formulating the composition in a unit dosage form for ease of administration to the subject.
Regarding the amount of telomerase inhibitor in the composition in unit dosage form, Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg (lines 34-59 of column 34,). Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 78 mg to 1014 mg (women) or from 91 mg to 1183 mg (men). The upper bound of the range for men is less than the lower bound of the instantly claimed range of about 1500 mg to about 3000 mg.
Stuart also teaches that the telomerase inhibitor compounds are effective over a wide dosage range and that the amount of telomerase inhibitor compounds administered will be determined by a physician based on the chosen route of administration and other factors (age, weight, patient response, symptom severity). See lines 32-41 of column 23.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of imetelstat in the unit dosage form of claims 1-16 of ‘938 modified by Bookbinder. The person of ordinary skill in the art would have had a reasonable expectation of success in following Stuart’s recommendations.
Regarding claim 102, claims 1-16 of ‘938 do not recite that the imetelstat is in a kit with rHuPH20.
It would have been obvious to formulate the composition of claims 1-16 of ‘938 modified by Bookbinder and Stuart in a kit comprising telomerase inhibitor imetelstat and an effective amount of the hyaluronidase enzyme rHuPH20 to enhance the systemic distribution of imetelstat. One of ordinary skill in the art would have recognized the benefit of formulating the composition in a kit for the ease of retail to the customer (e.g. a medical clinic).
Regarding the amount of telomerase inhibitor in the composition in the kit, Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg (lines 34-59 of column 34,). Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 78 mg to 1014 mg (women) or from 91 mg to 1183 mg (men). The upper bound of the range for men is less than the lower bound of the instantly claimed range of about 1500 mg to about 3000 mg.
Stuart also teaches that the telomerase inhibitor compounds are effective over a wide dosage range and that the amount of telomerase inhibitor compounds administered will be determined by a physician based on the chosen route of administration and other factors (age, weight, patient response, symptom severity). See lines 32-41 of column 23.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of imetelstat in the kit of claims 1-16 of ‘938 modified by Bookbinder. The person of ordinary skill in the art would have had a reasonable expectation of success in following Stuart’s recommendations.
Claims 1, 4-9, 12-17, 20-23, 30-32, and 138 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 8,877,723 (hereafter ‘723) in view of Stuart et al. (US 9,375,485 B2) and Bookbinder et al. (US 7,767,429 B2), Frost et al. (Expert opinion on drug delivery 4.4 (2007): 427-440; cited in the Non-Final Action mailed on 4/24/2024), and Soane and as evidenced by Hanczyc et al. (Langmuir, 2012, Vol. 28, pp. 6662−6669), by Centers for Disease Control (2021, website; cited in the Non-Final Action mailed on 12/30/2022), and by ClinicalTrials.gov (2021, website; cite din the Non-Final Action mailed on 12/30/2022).
Claim 1 of ‘723 is drawn to a method to treat a patient with a telomerase inhibitor comprising administering a reduced dose of the telomerase inhibitor. Claims 2-17 further limit the method of claim 1.
Claim 10 of ‘723 recites that the dosage regimen of GRN163L comprises administration of at least about 1.6 mg/kg to about 20 mg/kg of GRN163L on day 1 and on approximately day 8 of a 21 day cycle.
Claim 9 of ‘723 requires that the telomerase inhibitor is GRN163L. GRN163L is imetelstat, as evidenced by ClinicalTrials.gov (see Study Design, Official Title, page 3).
Claim 12 of ‘723 requires that the patient is being treated for cancer.
Claims 1-17 of ‘723 do not recite the structure of the telomerase inhibitor.
Stuart teaches a telomerase inhibitor comprising an oligonucleotide (column 4, lines 12-14) further comprising a lipid moiety linked to the 5' and/or 3' end of the oligonucleotide (column 4, lines 24-27). Stuart teaches a method for reducing neoplastic progenitor cell proliferation in an individual diagnosed with or suspected of having myelofibrosis or myelodysplastic syndrome (a rare cancer, see Stuart lines 6-7 of column 3) comprising administering a telomerase inhibitor (Stuart claim 6) comprising an oligonucleotide wherein the oligonucleotide comprising a lipid moiety linked to the 5' and/or 3' end of the oligonucleotide (Stuart claims 11 and 17). The composition may be injected subcutaneously (column 32, lines 46-47). Stuart’s telomerase inhibitor is GRN163L, also called imetelstat (see lines 12-13 of column 14).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to apply Stuart’s teachings regarding the structure of the telomerase inhibitor GRN163L to the method of claims 1-17 of ‘723. Claim 3 of ‘723 indicates that the telomerase inhibitor is GRN163L but does not specify the structure. Stuart defines the structure of GRN163L. Therefore, the person of ordinary skill in the art would have had a reasonable expectation of success that the telomerase inhibitor of claims 1-17 of ‘723 possessed the same properties as Stuart’s telomerase inhibitor.
Claims 1-17 of ‘723 do not recite that the composition further comprises an effective amount of the hyaluronidase enzyme rHuPH20.
Bookbinder teaches human soluble PH20 hyaluronidase glycoproteins or sHASEGPs (column 3, lines 51-54). Bookbinder teaches rHuPH20, which is a recombinant human hyaluronidase enzyme, in Example 14 (line 15 of column 97). Thus, Bookbinder’s sHASEGPs are soluble recombinant forms of human hyaluronidase PH20 (rHuPH20). Bookbinder teaches that subcutaneous administration of molecules in the presence of sHASEGPs facilitates their rapid systemic distribution (column 8, lines 30-33). Bookbinder teaches that sHASEGPs open channels in the interstitial space through degradation of glycosaminoglycans (column 8, lines 2-5) and that these channels facilitate the diffusion of small molecules, proteins, and nucleic acids less than 500 nm in size (column 8, lines 6-10). Bookbinder teaches further that temporary removal of glycosaminoglycans enhances the delivery of drugs into interstitial spaces, which facilitates diffusion of therapeutic molecules and proteins (column 8, lines 26-30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the telomerase inhibitor imetelstat of claims 1-17 of ‘723 and with the hyaluronidase enzyme rHuPH20 of Bookbinder in an effective amount to enhance systemic distribution of the telomerase inhibitor for the treatment of cancer. One of ordinary skill would have had a reasonable expectation of success given the teaching of Bookbinder that sHASEGPs (a species of hyaluronidase enzyme) facilitated the diffusion of many forms of therapeutic molecules and proteins, including small molecules, proteins, and nucleic acids, as long as they were less than 500 nm in size. Because the telomerase inhibitor of claims 1-17 of ‘723 and Stuart was an oligonucleotide comprising only 13 nucleotides (column 4, line 19 of Stuart) and lipid moiety up to 16 carbons in length (column 4, lines 31-32 of Stuart), it would have been obvious to one of ordinary skill that the oligonucleotide (telomerase inhibitor) of claims 1-17 of ‘723 and Stuart was less than the 500 nm size limit taught by Bookbinder, as evidenced by Hanczyc (see Abstract of Hanczyc: an oligonucleotide less than 60 bases is less than 20.4 nm in size).
Claim 10 of ‘723 recites that the telomerase inhibitor may be administered in a range of dosages 1.6 mg/kg to 20 mg/kg. Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), claim 10 of ‘723 suggests that the telomerase inhibitor may be administered in a range of dosages from 124.8 mg to 1560 mg (women) or from 145.6 mg to 1820 mg (men). The upper bound of the range for men overlaps with the instantly claimed range of 1500 mg to 3000 mg.
Claims 1-17 of ‘723 do not recite that the imetelstat is in a unit dosage.
However, Stuart teaches that a telomerase inhibitor composition may be formulated in a unit dosage form (column 22, lines 48-49 and column 23, lines 19-20). Therefore, it would have been obvious to formulate imetelstat in unit dosage form in the composition of claims 1-17 of ‘723 modified by Stuart and Bookbinder per the teaching of Stuart. The person of ordinary skill in the art would have had a reasonable expectation of success in this formulation.
Claims 1-17 of ‘723 do not recite and Stuart and Bookbinder do not teach that the composition provides a therapeutically effective pharmacokinetic profile for the telomerase inhibitor when co-formulated with the recombinant human hyaluronidase enzyme.
Frost teaches that recombinant human hyaluronidase (rHuPH20) enables subcutaneous drug and fluid administration (Title). Specifically, Frost teaches that molecules up to several hundred nanometers in diameter are readily dispersed by co-administration with rHuPH20 and the pharmacokinetic profile of molecules co-injected with rHuPH20 results in a higher Cmax and earlier Tmax than when injected with carrier controls (page 437, right column, paragraph 3). Frost teaches that driving the pharmacokinetic profile from a traditional subcutaneous absorption curve towards an intravenous-like bolus profile may be valuable when peak blood levels and time to onset are critical to achieve the desired clinical response (page 438, right column, 5.2 Modified pharmacokinetics following subcutaneous injection with rHuPH20)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the amount of rHuPH20 in the composition of claims 1-17 of ‘723, Bookbinder, and Stuart such that the composition would have had an effective pharmacokinetic profile when administered subcutaneously. The person of ordinary skill in the art would have had a reasonable expectation of success based on the teaching of Frost, which suggested that rHuPH20 in combination with molecules up to several hundred nanometers in diameter confers favorable pharmacokinetics.
Claims 1-17 of ‘723 do not recite and Stuart, Bookbinder, and Frost do not teach that the composition further comprises methionine or histidine.
Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27). The concentration of histidine in the buffer is also 50 mM based on the 1:1 stoichiometry of histidine to hydrochloride. The adjusted pH of the buffered formulations is 6.0 (paragraph 115, line 30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to buffer the formulation of claims 1-17 of ‘723 modified by Stuart, Bookbinder, and Frost using the histidine hydrochloride buffer taught by Soane. One of ordinary skill in the art would have been motivated to use a slightly acidic buffer system (such as pH 6.0) based on the activity of the human PH20 hyaluronidase enzyme, which has an optimal pH at acidic to neutral conditions (Bookbinder column 25, lines 57-61).
Pertaining to claims 4 and 7-8, Bookbinder teaches truncation of the hydrophobic C-terminus of human recombinant PH20 enzyme (column 86, Example 4, lines 7 and 18-20). Bookbinder teaches that the truncation may occur at residues P478, Q479, 1480, F481, Y482 (column 87, lines 14-15), or N483 (column 86, line 64). Thus, Bookbinder teaches a fragment of the PH20 enzyme. One of ordinary skill in the art would have been motivated before the effective filing date of the claimed invention to use the truncated human recombinant PH20 enzyme taught by Bookbinder in the combination of hyaluronidase enzyme rHuPH20 (Bookbinder) and telomerase inhibitor imetelstat (Stuart) discussed above in order to improve the solubility of the combination by removing the hydrophobic tail of hyaluronidase enzyme, as taught by Bookbinder.
Pertaining to claims 5-6 and 9, Bookbinder claim 1 recites “a hyaluronidase glycoprotein that consists of the sequence of amino acids set forth as amino acids 1-477, 36-477, 1-478, 36-478, 1-479, 36-479, 1-480, 36-480, 1-481, 36-481, 1-482, 36-482, 1-483 or 36-483 of 40 SEQ ID NO: 1,” wherein SEQ ID NO: 1 is 100% identical to the instant SEQ ID NO: 1, which represents the amino acid sequence of PH20. Thus, Bookbinder teaches N-terminal truncations of PH20 with a cleavage position before amino acid residue L36 and specifically teaches the PH20 fragment of 36-482. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the N-terminal truncations of PH20 taught by Bookbinder in the combination of claims 1-17 of ‘723, Stuart, and Bookbinder. One of ordinary skill in the art would have recognized that the N-terminal leader sequence would not have been required for the enzymatic activity of the PH20 enzyme because the leader sequence would have been removed during cellular production prior to purification, as taught by Bookbinder (Example 9, Purification of sHASEGP, column 93, lines 4-6).
Pertaining to claims 12-13, Bookbinder teaches an embodiment in which a hyaluronidase domain of a sHASEGP polypeptide, or a catalytically active portion thereof, does not include the entire sequence of amino acids set forth in SEQ ID NO: 1 but is at least 90% or 95% identical to SEQ ID NO: 1 (column 6, lines 25-29), wherein SEQ ID NO: 1 of Bookbinder is identical to the instant SEQ ID NO: 1 (the amino acid sequence of wild-type PH20).
Regarding claim 14, Bookbinder teaches unit dosage forms of a hyaluronidase enzyme, such as 1 to 5,000 Units of the enzyme in a small volume (column 59, lines 31-33) that are suitable for administration to a human (column 59, lines 9-12). 1 to 5,000 Units of a hyaluronidase enzyme overlaps with 100 U to 50,000 U. Bookbinder also teaches that the unit dosage (1 to 5,000 units of the enzyme) can be prepackaged in a syringe for use, such as after viscoelastic injection (column 59, lines 34-35), which is a form of subcutaneous injection. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine a unit dosage of a hyaluronidase enzyme at a known and tolerated dosage acceptable for subcutaneous administration in a human with the telomerase inhibitor of claims 1-17 of ‘723 and Stuart in order to facilitate diffusion of the telomerase inhibitor, as discussed above. One of ordinary skill would have had a reasonable expectation of success given that the dosage of hyaluronidase enzyme taught by Bookbinder was formulated for subcutaneous administration.
Pertaining to claim 15, claims 1-17 of ‘723 do not recite that the composition further comprises a pharmaceutically acceptable excipient.
Stuart teaches that the telomerase inhibitor is administered with a pharmaceutically acceptable excipient (column 4, lines 34-36).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to apply Stuart’s teaching regarding including a pharmaceutically acceptable excipient to the composition of claims 1-17 of ‘723, Stuart, and Bookbinder. The person of ordinary skill in the art would have been motivated to do so and had a reasonable expectation of success because both claims 1-17 of ‘723 and Stuart’s teachings were drawn to a method of cancer treatment comprising administering a telomerase inhibitor such as imetelstat (see Stuart claim 1 and claims 9 and 12 of ‘723).
Pertaining to claim 16 -17, claims 1-17 of ‘723 do not require that the composition comprising a telomerase inhibitor further comprises saccharides.
Stuart teaches that the telomerase inhibitor is administered as an aqueous solution with dissolution enhancers including 10% dextrose (a saccharide). A 10% dextrose solution is approximately 555 mM of saccharide, which is slightly above the claimed range of 10 mM to 500 mM. Therefore, a prima facie case of obviousness exists. See MPEP 2144.05.
Pertaining to claim 21, claims 1-17 of ‘723 do not require that the composition comprising a telomerase inhibitor further comprises a buffer.
Stuart teaches that the telomerase inhibitor is administered with a buffer (column 33, lines 7-8).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to apply Stuart’s teaching regarding including saccharides and a buffer to the composition of claims 1-17 of ‘723, Stuart, and Bookbinder. The person of ordinary skill in the art would have been motivated to do so and would have had a reasonable expectation of success because both claims 1-17 of ‘723 and Stuart’s teachings were drawn to a method of cancer treatment comprising administering a telomerase inhibitor such as imetelstat (see Stuart claim 1 and claims 9 and 12 of ‘723).
Pertaining to claim 20, Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27). The concentration of histidine in the buffer is also 50 mM based on the 1:1 stoichiometry of histidine to hydrochloride. 50 mM is within the claimed range of from 1 mM to 100 mM.
Pertaining to claims 22-23, Bookbinder teaches that sHASEGP glycoproteins (hyaluronidase enzymes) are neutral active in vitro at pH between 5 and 8 under conditions of salt less than 150 mM and buffering strength less than 50 mM (column 25, lines 57-61). A buffering strength less than 50 mM overlaps with the claimed range of 1 to 100 mM. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to formulate a composition comprising both sHASEGP and a telomerase inhibitor at acidic pH 5 to 8 in order to maintain the activity of the hyaluronidase enzyme. pH 5 to 8 overlaps with the claimed range of pH 3.0 to 9.0.
Regarding claim 30, claim 10 of ‘723 recites that the administration of GRN163L (the telomerase inhibitor imetelstat) is at least about 1.6 mg/kg to about 20 mg/kg. This range overlaps with the instantly claimed range (about 17.0 mg/kg to 20 mg/kg). Therefore, a case of prima facie obviousness exists. See MPEP 2144.05.
Regarding claim 31, claim 10 of ‘723 recites that the telomerase inhibitor may be administered in a range of dosages 1.6 mg/kg to 20 mg/kg. Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), the dosage recited in claim 10 of ‘723 is equivalent to from 124.8 mg to 1560 mg (women) or from 145.6 mg to 1820 mg (men). The dosages for men and women overlap with the instantly claimed range of about 1500 mg to about 1600 mg.
Regarding claim 32, claims 1-17 of ‘723 do not recite that the composition is lyophilized.
In lines 45-46 and 65-66 of column 22, Stuart teaches that the active ingredient (telomerase inhibitor) may be lyophilized (claim 32). Similarly, Bookbinder teaches that sHASEGP (a hyaluronidase enzyme) may be prepared as a lyophilized powder (Bookbinder, column 65, lines 31-32). Since both the telomerase inhibitor and the hyaluronidase enzyme may be prepared in lyophilized forms, it would have been obvious to one of ordinary skill in the art to formulate a composition comprising both components in lyophilized form.
Regarding claim 138, claims 1-17 of ‘723 do not recite that the telomerase inhibitor dosage is about 1500 mg to 2500 mg.
Stuart teaches that telomerase inhibitor compounds are effective over a wide dosage range and are generally administered in a therapeutically effective amount (Stuart, lines 32-34 of column 23). Stuart teaches: “It will be understood, however, that the amount of the telomerase inhibitor compounds actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms and the like” (Stuart, lines 32-41 of column 23). Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of imetelstat in the composition of claims 1-17 of ‘723 modified by Stuart, Bookbinder, Frost, and Soane based on the variables taught by Stuart and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
Claim 10 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 8,877,723 (hereafter ‘723) in view of Stuart, Bookbinder, Frost, and Soane and as evidenced by Hanczyc, Centers for Disease Control, and ClinicalTrials.gov, as applied to claims 1, 4-9, 12-17, 20-23, 30-32, and 138 above, further in view of Pecceu et al. (Genes Vol. 97, 1991, pp. 23-258).
See discussion of claims 1-17 of ‘723, Stuart, Bookbinder, Frost, and Soane above, which is incorporated into this rejection as well. Bookbinder teaches enhanced mammalian expression systems using signal leaders capable of efficient secretion of sHASEGP (column 5, lines 51-53).
Claims 1-17 of ‘723 do not recite and Stuart and Bookbinder do not teach that N-terminus of the PH20 fragment comprises a human growth hormone-derived signal peptide.
Pecceu teaches that human interleukin 1β fused to the human growth hormone signal peptide is secreted by Chinese hamster ovary cells (Title). The sequence of the human growth hormone signal peptide is given in Figure 1B and is identical to SEQ ID NO: 3 of the instant application. Fig. 2 demonstrates the signal peptide nucleotide sequence is fused to the N-terminus of the gene.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to further modify the PH20 enzyme fragment in the composition of claims 1-17 of ‘723 modified by Stuart, Bookbinder, Frost, and Soane such that the enzyme could be produced in a mammalian expression system. One skilled in the art would have recognized that the secretion of the PH20 enzyme fragment would have required a signal peptide recognized by the expression system. One of ordinary skill in the art would have been motivated to use the human growth factor-derived signal peptide taught by Pecceu because of its demonstrated success in recombinant protein expression by Chinese hamster ovary cells.
Claims 70 and 102 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 8,877,723 (hereafter ‘723) in view of Stuart, Bookbinder, and Soane and as evidenced by Hanczyc, Centers for Disease Control, and ClinicalTrials.gov.
See discussion of claims 1-17 of ‘723, Stuart, and Bookbinder above, which is incorporated into this rejection as well.
Claims 1-17 of ‘723 do not recite and Stuart, Bookbinder, and Frost do not teach that the composition further comprises methionine or histidine.
Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27). The concentration of histidine in the buffer is also 50 mM based on the 1:1 stoichiometry of histidine to hydrochloride. The adjusted pH of the buffered formulations is 6.0 (paragraph 115, line 30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to buffer the formulation of claims 1-17 of ‘723 modified by Stuart, Bookbinder, and Frost using the histidine hydrochloride buffer taught by Soane. One of ordinary skill in the art would have been motivated to use a slightly acidic buffer system (such as pH 6.0) based on the activity of the human PH20 hyaluronidase enzyme, which has an optimal pH at acidic to neutral conditions (Bookbinder column 25, lines 57-61).
Pertaining to claim 70, claims 1-17 of ‘723 do not recite that the composition is in unit dosage form.
Stuart teaches that a telomerase inhibitor composition may be formulated in a unit dosage form (column 22, lines 48-49 and column 23, lines 19-20). Bookbinder teaches that sHASEGP polypeptides (human hyaluronidase enzymes) may be formulated in unit dosage forms (column 58, lines 59 and 67 and column 59, line 1). It would have been obvious to formulate the composition of claims 1-17 of ‘723 modified by Stuart and Bookbinder in unit dosage form comprising telomerase inhibitor imetelstat and an effective amount of the hyaluronidase enzyme rHuPH20 to enhance the systemic distribution of imetelstat. One of ordinary skill in the art would have recognized the benefit of formulating the composition in a unit dosage form for ease of administration to the subject.
Regarding the amount of telomerase inhibitor in the composition in unit dosage form, claim 10 of ‘723 recites that the telomerase inhibitor may be administered in a range of dosages 1.6 mg/kg to 20 mg/kg. Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), the dosage recited in claim 10 of ‘723 is equivalent to from 124.8 mg to 1560 mg (women) or from 145.6 mg to 1820 mg (men). The dosages for men and women overlap with the instantly claimed range of about 1500 mg to about 1600 mg.
Regarding claim 102, claims 1-17 of ‘723 do not recite that the composition is in a kit.
It would have been obvious to formulate the composition of claims 1-17 of ‘723 modified by Stuart and Bookbinder in a kit comprising telomerase inhibitor imetelstat and an effective amount of the hyaluronidase enzyme rHuPH20 to enhance the systemic distribution of imetelstat. One of ordinary skill in the art would have recognized the benefit of formulating the composition in a kit for the ease of retail to the customer (e.g. a medical clinic).
Regarding the amount of telomerase inhibitor in the composition in the kit, claim 10 of ‘723 recites that the telomerase inhibitor may be administered in a range of dosages 1.6 mg/kg to 20 mg/kg. Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), the dosage recited in claim 10 of ‘723 is equivalent to from 124.8 mg to 1560 mg (women) or from 145.6 mg to 1820 mg (men). The dosages for men and women overlap with the instantly claimed range of about 1500 mg to about 1600 mg.
Claims 1, 4-9, 12-17, 20-23, 30-32, and 138 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 9,155,753 (hereafter ‘753) in view of Stuart et al. (US 9,375,485 B2), Bookbinder et al. (US 7,767,429 B2), Frost et al. (Expert opinion on drug delivery 4.4 (2007): 427-440; cited in the Non-Final Action mailed on 4/24/2024), and Soane, and as evidenced by Hanczyc et al. (Langmuir, 2012, Vol. 28, pp. 6662−6669), by Centers for Disease Control (2021), and by ClinicalTrials.gov (2012, cited in the Non-Final Action mailed on 12/30/2022).
Claim 1 of ‘753 is drawn to a method for inhibiting the proliferation of carcinoma cells that express an EGF receptor comprising exposing the cells to an anti-EGF receptor antibody trastuzumab and exposing the cells to a telomerase inhibitor comprising an oligonucleotide which is characterized by: (i) N3'→P5' thiophosphoramidate internucleoside linkages; (ii) comprising the sequence identified as SEQ ID NO: 12; and (iii) a palmitoyl (C16) moiety linked to the 5' terminus of the oligonucleotide via a glycerol or aminoglycerol linker.
Claim 2 of ‘753 limits the oligonucleotide to 13-20 bases in length.
Claim 3 of ‘753 limits the telomerase inhibitor to GRN163L.
Claims 4-5 of ‘753 further limit the method of claim 1 of ‘753.
Therefore, claims 1-5 of ‘753 are drawn to a method of administering a comprising a telomerase inhibitor to treat a cancer. Claims 1-5 of ‘753 do not recite that the composition comprises an effective amount of hyaluronidase enzyme rHuPH20.
The telomerase inhibitor GRN163L (claim 3 of ‘753) is imetelstat, as evidenced by ClinicalTrials.gov (see Study Design, Official Title on page 3).
Bookbinder teaches human soluble PH20 hyaluronidase glycoproteins or sHASEGPs (column 3, lines 51-54). Bookbinder teaches rHuPH20, which is a recombinant human hyaluronidase enzyme, in Example 14 (line 15 of column 97). Thus, Bookbinder’s sHASEGPs are soluble recombinant forms of human hyaluronidase PH20 (rHuPH20). Bookbinder teaches that subcutaneous administration of molecules in the presence of sHASEGPs facilitates their rapid systemic distribution (column 8, lines 30-33). Bookbinder teaches that sHASEGPs open channels in the interstitial space through degradation of glycosaminoglycans (column 8, lines 2-5) and that these channels facilitate the diffusion of small molecules, proteins, and nucleic acids less than 500 nm in size (column 8, lines 6-10). Bookbinder teaches further that temporary removal of glycosaminoglycans enhances the delivery of drugs into interstitial spaces, which facilitates diffusion of therapeutic molecules and proteins (column 8, lines 26-30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the telomerase inhibitor imetelstat of claims 1-5 of ‘753 with the hyaluronidase enzyme rHuPH20 of Bookbinder in an effective amount to enhance systemic distribution of the telomerase inhibitor for the treatment of cancer. One of ordinary skill in the art would have had a reasonable expectation of success given the teaching of Bookbinder that sHASEGPs (a species of hyaluronidase enzyme) facilitates the diffusion of many forms of therapeutic molecules and proteins, including small molecules, proteins, and nucleic acids, as long as they are less than 500 nm in size. Because the telomerase inhibitor of claims 1-5 of ‘753 is an oligonucleotide comprising only 13-20 nucleotides (claim 2 of ‘753) and lipid moiety up to 16 carbons in length (claim 1 of ‘753), it would have been obvious to one of ordinary skill that the oligonucleotide (the telomerase inhibitor imetelstat) of claims 1-5 of ‘753 is less than the 500 nm size limit taught by Bookbinder, as evidenced by Hanczyc (see Abstract of Hanczyc: an oligonucleotide less than 60 bases is less than 20.4 nm in size).
Claims 1-5 of ‘753 do not recite that the composition comprises 1500 mg to 3000 mg of imetelstat in a unit dosage.
Stuart teaches a telomerase inhibitor comprising an oligonucleotide (column 4, lines 12-14) further comprising a lipid moiety linked to the 5' and/or 3' end of the oligonucleotide (column 4, lines 24-27). Stuart teaches a method for reducing neoplastic progenitor cell proliferation in an individual diagnosed with or suspected of having myelofibrosis or myelodysplastic syndrome (a rare cancer, see Stuart lines 6-7 of column 3) comprising administering a telomerase inhibitor (Stuart claim 6) comprising an oligonucleotide wherein the oligonucleotide comprising a lipid moiety linked to the 5' and/or 3' end of the oligonucleotide (Stuart claims 11 and 17). The composition may be injected subcutaneously (column 32, lines 46-47). Stuart’s telomerase inhibitor is GRN163L, also called imetelstat (see lines 12-13 of column 14).
Stuart’s telomerase inhibitor is the same as the telomerase inhibitor in claims 1-5 of ‘753 and the inhibitor is also for the treatment of cancer.
In lines 34-59 of column 34, Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg. Stuart teaches that a telomerase inhibitor composition may be formulated in a unit dosage form (column 22, lines 48-49 and column 23, lines 19-20). Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 78 mg to 1014 mg (women) or from 91 mg to 1183 mg (men). The upper bound of Stuart’s range for men is less than the instantly claimed range of 1500 mg to 3000 mg.
Stuart also teaches that the telomerase inhibitor compounds are effective over a wide dosage range and that the amount of telomerase inhibitor compounds administered will be determined by a physician based on the chosen route of administration and other factors (age, weight, patient response, symptom severity). See lines 32-41 of column 23.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the dosage of imetelstat per Stuart’s teaching in the composition of claims 1-5 of ‘753 modified by Bookbinder. The person of ordinary skill in the art would have been motivated to do so and had a reasonable expectation of success because the claims 1-5 of ‘753 and Stuart were both drawn to a method of treatment of cancer comprising administering a telomerase inhibitor (see Stuart claim 1 and claims 1-5 of ‘753).
Claims 1-5 of ‘753 do not recite and Stuart and Bookbinder do not teach that the composition provides a therapeutically effective pharmacokinetic profile for the telomerase inhibitor when co-formulated with the recombinant human hyaluronidase enzyme.
Frost teaches that recombinant human hyaluronidase (rHuPH20) enables subcutaneous drug and fluid administration (Title). Specifically, Frost teaches that molecules up to several hundred nanometers in diameter are readily dispersed by co-administration with rHuPH20 and the pharmacokinetic profile of molecules co-injected with rHuPH20 results in a higher Cmax and earlier Tmax than when injected with carrier controls (page 437, right column, paragraph 3). Frost teaches that driving the pharmacokinetic profile from a traditional subcutaneous absorption curve towards an intravenous-like bolus profile may be valuable when peak blood levels and time to onset are critical to achieve the desired clinical response (page 438, right column, 5.2 Modified pharmacokinetics following subcutaneous injection with rHuPH20)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the amount of rHuPH20 in the composition of claims 1-5 of ‘753 modified by Bookbinder and Stuart such that the composition would have had an effective pharmacokinetic profile when administered subcutaneously. The person of ordinary skill in the art would have had a reasonable expectation of success based on the teaching of Frost, which suggested that rHuPH20 in combination with molecules up to several hundred nanometers in diameter confers favorable pharmacokinetics.
Claims 1-5 of ‘753 do not recite and Bookbinder, Stuart, and Frost do not teach that the composition further comprises methionine or histidine.
Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27). The concentration of histidine in the buffer is also 50 mM based on the 1:1 stoichiometry of histidine to hydrochloride. The adjusted pH of the buffered formulations is 6.0 (paragraph 115, line 30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to buffer the formulation of claims 1-5 of ‘753 modified by Bookbinder, Stuart, and Frost using the histidine hydrochloride buffer taught by Soane. One of ordinary skill in the art would have been motivated to use a slightly acidic buffer system (such as pH 6.0) based on the activity of the hyaluronidase enzyme, which has an optimal pH at acidic to neutral conditions (Bookbinder column 25, lines 57-61).
Pertaining to claims 4 and 7-8, Bookbinder teaches truncation of the hydrophobic C-terminus of recombinant PH20 enzyme (column 86, Example 4, lines 7 and 18-20). Bookbinder teaches that the truncation may occur at residues P478, Q479, 1480, F481, Y482 (column 87, lines 14-15), N483 (column 86, line 64).Thus, Bookbinder teaches a fragment of the PH20 enzyme. One of ordinary skill in the art would have been motivated before the effective filing date of the claimed invention to use the truncated recombinant PH20 enzyme taught by Bookbinder in the combination of hyaluronidase enzyme (Bookbinder) and telomerase inhibitor (claims 1-5 of ‘753) discussed above in order to improve the solubility of the combination by removing the hydrophobic tail of hyaluronidase enzyme, as taught by Bookbinder.
Pertaining to claims 5-6 and 9, Bookbinder claim 1 recites “a hyaluronidase glycoprotein that consists of the sequence of amino acids set forth as amino acids 1-477, 36-477, 1-478, 36-478, 1-479, 36-479, 1-480, 36-480, 1-481, 36-481, 1-482, 36-482, 1-483 or 36-483 of 40 SEQ ID NO: 1,” wherein SEQ ID NO: 1 is 100% identical to the instant SEQ ID NO: 1, which represents the amino acid sequence of PH20. Thus, Bookbinder teaches N-terminal truncations of PH20 with a cleavage position before amino acid residue L36 and specifically teaches the PH20 fragment of 36-482. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the N-terminal truncations of PH20 taught by Bookbinder in the combination of claims 1-5 of ‘753 and Bookbinder. One of ordinary skill would have recognized that the N-terminal leader sequence would not have been required for the enzymatic activity of the PH20 enzyme because the leader sequence would have been removed during cellular production prior to purification, as taught by Bookbinder (Example 9, Purification of sHASEGP, column 93, lines 4-6).
Pertaining to claims 12-13, Bookbinder teaches an embodiment in which a hyaluronidase domain of a sHASEGP polypeptide, or a catalytically active portion thereof, does not include the entire sequence of amino acids set forth in SEQ ID NO: 1 but is at least 90% or 95% identical to SEQ ID NO: 1 (column 6, lines 25-29), wherein SEQ ID NO: 1 of Bookbinder is identical to the instant SEQ ID NO: 1 (the amino acid sequence of wild-type PH20).
Regarding claim 14, Bookbinder teaches unit dosage forms of a hyaluronidase enzyme, such as 1 to 5,000 Units of the enzyme in a small volume (column 59, lines 31-33) that are suitable for administration to a human (column 59, lines 9-12). 1 to 5,000 Units of a hyaluronidase enzyme overlaps with 100 U to 50,000 U. Bookbinder also teaches that the unit dosage (1 to 5,000 units of the enzyme) can be prepackaged in a syringe for use, such as after viscoelastic injection (column 59, lines 34-35), which is a form of subcutaneous injection. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine a unit dosage of a hyaluronidase enzyme at a known and tolerated dosage acceptable for subcutaneous administration in a human with the telomerase inhibitor of Stuart in order to facilitate diffusion of the telomerase inhibitor, as discussed above. One of ordinary skill would have had a reasonable expectation of success given that the dosage of hyaluronidase enzyme taught by Bookbinder was formulated for subcutaneous administration.
Pertaining to claim 15, claims 1-5 of ‘753 do not recite and Bookbinder does not teach that the composition further comprises a pharmaceutically acceptable carrier.
Stuart teaches that the telomerase inhibitor is administered with a pharmaceutically acceptable excipient (column 4, lines 34-36).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to apply Stuart’s teaching regarding including a pharmaceutically acceptable excipient to the composition of claims 1-5 of ‘753 modified by Bookbinder, Stuart, and Frost. The person of ordinary skill in the art would have been motivated to do so and had a reasonable expectation of success because both claims 1-5 of ‘753 and Stuart’s teachings were drawn to a method of cancer treatment comprising administering a telomerase inhibitor (see Stuart claim 1 and claims 1-5 of ‘753).
Pertaining to claims 16-17, claims 1-5 of ‘753 do not recite that the composition comprising a telomerase inhibitor further comprises polysaccharides.
Stuart teaches that the telomerase inhibitor is administered as an aqueous solution with dissolution enhancers including 10% dextrose (a saccharide). A 10% dextrose solution is approximately 555 mM of saccharide, which is slightly above the claimed range of 10 mM to 500 mM. Therefore, a prima facie case of obviousness exists. See MPEP 2144.05.
Pertaining to claim 21, claims 1-5 of ‘753 d not recite that the composition comprising a telomerase inhibitor further comprises a buffer.
Stuart teaches that the telomerase inhibitor is administered with a buffer (column 33, lines 7-8).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to apply Stuart’s teaching regarding including saccharides and a buffer to the composition of claims 1-5 of ‘753 modified by Bookbinder, Stuart, and Frost. The person of ordinary skill in the art would have been motivated to do so and had a reasonable expectation of success because both claims 1-5 of ‘753 and Stuart’s teachings were drawn to a method of cancer treatment comprising administering a telomerase inhibitor (see Stuart claim 1 and claims 1-5 of ‘753).
Pertaining to claim 20, Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27). The concentration of histidine in the buffer is also 50 mM based on the 1:1 stoichiometry of histidine to hydrochloride. 50 mM is within the claimed range of from 1 mM to 100 mM.
Pertaining to claims 22-23, Bookbinder teaches that sHASEGP glycoproteins (hyaluronidase enzymes) are neutral active in vitro at pH between 5 and 8 under conditions of salt less than 150 mM and buffering strength less than 50 mM (column 25, lines 57-61). A buffering strength less than 50 mM overlaps with the claimed range of 1 to 100 mM. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to formulate a composition comprising both rHuPH20 and a telomerase inhibitor at acidic pH 5 to 8 in order to maintain the activity of the hyaluronidase enzyme. pH 5 to 8 overlaps with the claimed range of pH 3.0 to 9.0.
Regarding claim 30, claims 1-5 of ‘753 do not teach the dosage per body weight of imetelstat.
Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg (lines 34-59 of column 34). The lower bound of the instantly claimed range of about 17.0 mg/kg to 20.0 mg/kg is a value greater than the upper bound of Stuart’s range.
Stuart also teaches that the telomerase inhibitor compounds are effective over a wide dosage range and that the amount of telomerase inhibitor compounds administered will be determined by a physician based on the chosen route of administration and other factors (age, weight, patient response, symptom severity). See lines 32-41 of column 23.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the dosage per body weight of imetelstat per Stuart’s recommendations in the composition of claims 1-5 of ‘753 modified by Bookbinder, Stuart, and Frost. The person of ordinary skill in the art would have been motivated to do so and had a reasonable expectation of success because the claims 1-5 of ‘753 and Stuart are both drawn to a method of treatment of cancer comprising administering a telomerase inhibitor (see Stuart claim 1 and claims 1-5 of ‘753).
Regarding claim 31, claims 1-5 of ‘753 do not recite the telomerase inhibitor dosage.
In lines 34-59 of column 34, Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg. Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 78 mg to 1014 mg (women) or from 91 mg to 1183 mg (men). Stuart’s upper bound for men is a value less than the instantly claimed range of 1500 mg to 1600 mg.
Stuart also teaches that telomerase inhibitor compounds are effective over a wide dosage range and are generally administered in a therapeutically effective amount (Stuart, lines 32-34 of column 23). Stuart teaches: “It will be understood, however, that the amount of the telomerase inhibitor compounds actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms and the like” (Stuart, lines 32-41 of column 23).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the composition of claims 1-5 of ‘753 modified by Bookbinder, Stuart, and Frost based on the variables taught by Stuart and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
Regarding claim 32, claims 1-5 of ‘753 do not recite that the composition is lyophilized.
In lines 45-46 and 65-66 of column 22, Stuart teaches that the active ingredient (telomerase inhibitor) may be lyophilized. Similarly, Bookbinder teaches that sHASEGP (a hyaluronidase enzyme) may be prepared as a lyophilized powder (Bookbinder, column 65, lines 31-32). Since both the telomerase inhibitor and the hyaluronidase enzyme may be prepared in lyophilized forms, it would have been obvious to one of ordinary skill in the art to formulate a composition comprising both components in lyophilized form.
Regarding claim 138, claims 1-5 of ‘753 do not recite that the telomerase inhibitor dosage is about 1500 mg to 2500 mg (claim 138).
Stuart teaches that telomerase inhibitor compounds are effective over a wide dosage range and are generally administered in a therapeutically effective amount (Stuart, lines 32-34 of column 23). Stuart teaches: “It will be understood, however, that the amount of the telomerase inhibitor compounds actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms and the like” (Stuart, lines 32-41 of column 23). Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of imetelstat in the composition of claims 1-5 of ‘753 modified by Bookbinder based on the variables taught by Stuart and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
Claim 10 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 9,155,753 (hereafter ‘753) in view of Bookbinder, Stuart, Frost, and Soane and as evidenced by Hanczyc, Centers for Disease Control, and ClinicalTrials.gov, as applied to claims 1, 4-9, 12-17, 20-23, 30-32, and 138 above, further in view of Pecceu et al. (Genes Vol. 97, 1991, pp. 23-258).
See discussion of claims 1-5 of ‘753, Bookbinder, Stuart, Frost, and Soane above, which is incorporated into this rejection as well. Bookbinder teaches enhanced mammalian expression systems using signal leaders capable of efficient secretion of sHASEGP (column 5, lines 51-53).
Claims 1-5 of ‘753 do not recite that the N-terminus of the PH20 fragment comprises a human growth hormone-derived signal peptide.
Pecceu teaches that human interleukin 1β fused to the human growth hormone signal peptide is secreted by Chinese hamster ovary cells (Title). The sequence of the human growth hormone signal peptide is given in Figure 1B and is identical to SEQ ID NO: 3 of the instant application. Fig. 2 demonstrates the signal peptide nucleotide sequence is fused to the N-terminus of the gene.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to further modify the PH20 enzyme fragment in the composition of claims 1-5 of ‘753 modified by Bookbinder, Stuart, and Frost such that the enzyme could be produced in a mammalian expression system. One skilled in the art would have recognized that the secretion of the PH20 enzyme fragment would have required a signal peptide recognized by the expression system. One of ordinary skill would have been motivated to use the human growth factor-derived signal peptide taught by Pecceu because of its demonstrated success in recombinant protein expression by Chinese hamster ovary cells.
Claims 70 and 102 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 9,155,753 (‘753) in view of Bookbinder, Stuart, and Soane and as evidenced by Hanczyc, Centers for Disease Control, and ClinicalTrials.gov.
See discussion of claims 1-5 of ‘753, Bookbinder, and Stuart above, which is incorporated into this rejection as well.
Claims 1-5 of ‘753 do not recite and Bookbinder, Stuart, and Frost do not teach that the composition further comprises methionine or histidine.
Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27). The concentration of histidine in the buffer is also 50 mM based on the 1:1 stoichiometry of histidine to hydrochloride. The adjusted pH of the buffered formulations is 6.0 (paragraph 115, line 30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to buffer the formulation of claims 1-5 of ‘753 modified by Bookbinder, Stuart, and Frost using the histidine hydrochloride buffer taught by Soane. One of ordinary skill in the art would have been motivated to use a slightly acidic buffer system (such as pH 6.0) based on the activity of the hyaluronidase enzyme, which has an optimal pH at acidic to neutral conditions (Bookbinder column 25, lines 57-61).
Pertaining to claim 70, claims 1-5 of ‘753 do not recite that the composition is in unit dosage form.
Stuart teaches that a telomerase inhibitor composition may be formulated in a unit dosage form (column 22, lines 48-49 and column 23, lines 19-20). Bookbinder teaches that sHASEGP polypeptides (human hyaluronidase enzymes) may be formulated in unit dosage forms (column 58, lines 59 and 67 and column 59, line 1). It would have been obvious to formulate the composition of claims 1-5 of ‘723 modified by Bookbinder and Stuart in unit dosage form comprising telomerase inhibitor imetelstat and an effective amount of the hyaluronidase enzyme rHuPH20 to enhance the systemic distribution of imetelstat. One of ordinary skill in the art would have recognized the benefit of formulating the composition in a unit dosage form for ease of administration to the subject.
Regarding the amount of telomerase inhibitor in the composition in unit dosage form, Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg (lines 34-59 of column 34,). Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 78 mg to 1014 mg (women) or from 91 mg to 1183 mg (men). The upper bound of the range for men is less than the lower bound of the instantly claimed range of about 1500 mg to about 3000 mg.
Stuart also teaches that the telomerase inhibitor compounds are effective over a wide dosage range and that the amount of telomerase inhibitor compounds administered will be determined by a physician based on the chosen route of administration and other factors (age, weight, patient response, symptom severity). See lines 32-41 of column 23.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the imetelstat dosage in the composition in unit dosage form of claims 1-5 of ‘753 modified by Bookbinder per Stuart’s teaching. The person of ordinary skill in the art would have been motivated to do so and had a reasonable expectation of success because the claims 1-5 of ‘753 and Stuart were both drawn to a method of treatment of cancer comprising administering a telomerase inhibitor (see Stuart claim 1 and claims 1-5 of ‘753).
Regarding claim 102, claims 1-5 of ‘753 do not recite that the composition is in a kit.
It would have been obvious to formulate the composition of claims 1-5 of ‘753 modified by Bookbinder and Stuart in a kit comprising telomerase inhibitor imetelstat and an effective amount of the hyaluronidase enzyme rHuPH20 to enhance the systemic distribution of imetelstat. One of ordinary skill in the art would have recognized the benefit of formulating the composition in a kit for the ease of retail to the customer (e.g. a medical clinic).
Regarding the amount of telomerase inhibitor in the composition in the kit, Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 1 mg/kg to 13 mg/kg (lines 34-59 of column 34,). Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart teaches that the telomerase inhibitor may be administered in a range of dosages from 78 mg to 1014 mg (women) or from 91 mg to 1183 mg (men). The upper bound of the range for men is less than the lower bound of the instantly claimed range of about 1500 mg to about 3000 mg.
Stuart also teaches that the telomerase inhibitor compounds are effective over a wide dosage range and that the amount of telomerase inhibitor compounds administered will be determined by a physician based on the chosen route of administration and other factors (age, weight, patient response, symptom severity). See lines 32-41 of column 23.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the dosage of imetelstat in the kit of claims 1-5 of ‘753 Bookbinder and Stuart. The person of ordinary skill in the art would have had a reasonable expectation of success in the routine optimization of the dosage of imetelstat.
Claims 1, 4-9, 12-17, 20-23, 30-32, and 138 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-39 of U.S. Patent No. 12,171,778 (hereafter ‘778) in view of Bookbinder et al. (US 7,767,429 B2), Stuart et al. (US 9,375,485 B2), Frost et al. (Expert opinion on drug delivery 4.4 (2007): 427-440; cited in the Non-Final Action mailed on 4/24/2024), and Soane and as evidenced by Hanczyc et al. (Langmuir, 2012, Vol. 28, pp. 6662−6669) and by Centers for Disease Control (2021).
Claim 1 of ‘778 is drawn to a method comprising administering an effective amount of a telomerase inhibitor to the subject to treat myelodysplastic syndrome. Claims 2-21 of ‘778 further limit the method of claim 1.
Claim 16 of ‘778 recites that the telomerase inhibitor is imetelstat and is administered intravenously. Claim 17 of ‘778 recites that 7-10 mg/kg is administered. Claim 18 of ‘778 recites that 7.5 mg/kg is administered.
Claim 22 of ‘778 is drawn to administering an effective amount of a telomerase inhibitor to treat myelodysplastic syndrome. Claims 23-39 of ‘778 further limit the method of claim 22. Claim 23 of ‘778 limits the telomerase inhibitor to imetelstat. Claim 34 of ‘778 limits the imetelstat to imetelstat sodium. Claim 37 of ‘778 limits the administration to intravenous administration different dosages and frequencies of intravenous administration. Claim 38 of ‘778 limits the dosage to 7-10 mg/kg for intravenous administration. Claim 39 of ‘778 limits the dosage to 7.5 mg/kg for intravenous administration.
Therefore, claims 1-39 of ‘778 are drawn to a method of administering a comprising a telomerase inhibitor to treat a cancer (myelodysplastic syndrome is a type of blood cancer, see [0054] of the specification of ‘778). In some embodiments the telomerase inhibitor is imetelstat (see claims 16 and 23 of ‘778).
Claims 1-39 of ‘778 do not recite that the composition comprises an effective amount of hyaluronidase enzyme rHuPH20.
Bookbinder teaches human soluble PH20 hyaluronidase glycoproteins or sHASEGPs (column 3, lines 51-54). Bookbinder teaches rHuPH20, which is a recombinant human hyaluronidase enzyme, in Example 14 (line 15 of column 97). Thus, Bookbinder’s sHASEGPs are soluble recombinant forms of human hyaluronidase PH20 (rHuPH20). Bookbinder teaches that subcutaneous administration of molecules in the presence of sHASEGPs facilitates their rapid systemic distribution (column 8, lines 30-33). Bookbinder teaches that sHASEGPs open channels in the interstitial space through degradation of glycosaminoglycans (column 8, lines 2-5) and that these channels facilitate the diffusion of small molecules, proteins, and nucleic acids less than 500 nm in size (column 8, lines 6-10). Bookbinder teaches further that temporary removal of glycosaminoglycans enhances the delivery of drugs into interstitial spaces, which facilitates diffusion of therapeutic molecules and proteins (column 8, lines 26-30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the telomerase inhibitor imetelstat of claims 1-39 of ‘778 with the recombinant human hyaluronidase enzyme rHuPH20 of Bookbinder in an effective amount to enhance systemic distribution of the telomerase inhibitor for the treatment of cancer. One of ordinary skill in the art would have had a reasonable expectation of success given the teaching of Bookbinder that sHASEGPs (a species of hyaluronidase enzyme) facilitated the diffusion of many forms of therapeutic molecules and proteins, including small molecules, proteins, and nucleic acids, as long as they were less than 500 nm in size. Because the telomerase inhibitor of claims 1-39 of ‘778 was an oligonucleotide comprising only 13 nucleotides (see Stuart chemical formula in column 37) and lipid moiety up to 16 carbons in length (see Stuart chemical formula in column 37), it would have been obvious to one of ordinary skill that the oligonucleotide (the telomerase inhibitor imetelstat) of claims 1-39 of ‘778 is less than the 500 nm size limit taught by Bookbinder, as evidenced by Hanczyc (see Abstract of Hanczyc: an oligonucleotide less than 60 bases is less than 20.4 nm in size).
Claims 1-39 of ‘778 do not recite that the composition comprises about 1500 mg to about 3000 mg of imetelstat in a unit dosage. Rather, claims 16 and 37 of ‘778 recite dosages up to 10 mg/kg.
Given an average female weight of 78 kg and an average male weight of 91 kg, as evidenced by Centers for Disease Control (2021, Body Measurements), Stuart teaches that the telomerase inhibitor may be administered in a range of dosages up to 78 mg (women) or up to 910 mg (men), which is less than the instantly claimed range of 1500 mg to 3000 mg.
Stuart teaches a method for reducing neoplastic progenitor cell proliferation in an individual diagnosed with or suspected of having myelofibrosis or myelodysplastic syndrome comprising administering a telomerase inhibitor (Stuart claim 6) comprising an oligonucleotide wherein the oligonucleotide comprising a lipid moiety linked to the 5' and/or 3' end of the oligonucleotide (Stuart claims 11 and 17). The composition may be injected subcutaneously (column 32, lines 46-47). In lines 32-34 of column 4, Stuart teaches that the telomerase inhibitor is imetelstat. Stuart teaches that a telomerase inhibitor composition may be formulated in a unit dosage form (column 22, lines 48-49 and column 23, lines 19-20).
Stuart teaches that telomerase inhibitor compounds are effective over a wide dosage range and are generally administered in a therapeutically effective amount (Stuart, lines 32-34 of column 23). Stuart teaches: “It will be understood, however, that the amount of the telomerase inhibitor compounds actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms and the like” (Stuart, lines 32-41 of column 23).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the dosage of imetelstat in the composition of claims 1-39 of ‘778 modified by Bookbinder based on the variables taught by Stuart and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
Claims 1-39 of ‘778 do not recite and Bookbinder and Stuart do not teach that the composition provides a therapeutically effective pharmacokinetic profile for the telomerase inhibitor when co-formulated with the recombinant human hyaluronidase enzyme.
Frost teaches that recombinant human hyaluronidase (rHuPH20) enables subcutaneous drug and fluid administration (Title). Specifically, Frost teaches that molecules up to several hundred nanometers in diameter are readily dispersed by co-administration with rHuPH20 and the pharmacokinetic profile of molecules co-injected with rHuPH20 results in a higher Cmax and earlier Tmax than when injected with carrier controls (page 437, right column, paragraph 3). Frost teaches that driving the pharmacokinetic profile from a traditional subcutaneous absorption curve towards an intravenous-like bolus profile may be valuable when peak blood levels and time to onset are critical to achieve the desired clinical response (page 438, right column, 5.2 Modified pharmacokinetics following subcutaneous injection with rHuPH20)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the amount of rHuPH20 in the composition of claims 1-39 of ‘778 modified by Bookbinder and Stuart such that the composition would have had an effective pharmacokinetic profile when administered subcutaneously. The person of ordinary skill in the art would have had a reasonable expectation of success based on the teaching of Frost, which suggested that rHuPH20 in combination with molecules up to several hundred nanometers in diameter confers favorable pharmacokinetics.
Claims 1-39 of ‘778 do not recite and Bookbinder, Stuart, and Frost do not teach that the composition further comprises methionine or histidine.
Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27). The concentration of histidine in the buffer is also 50 mM based on the 1:1 stoichiometry of histidine to hydrochloride. The adjusted pH of the buffered formulations is 6.0 (paragraph 115, line 30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to buffer the formulation of claims 1-39 of ‘778 modified by Bookbinder, Stuart, and Frost using the histidine hydrochloride buffer taught by Soane. One of ordinary skill in the art would have been motivated to use a slightly acidic buffer system (such as pH 6.0) based on the activity of the hyaluronidase enzyme, which has an optimal pH at acidic to neutral conditions (Bookbinder column 25, lines 57-61).
Pertaining to claims 4 and 7-8, Bookbinder teaches truncation of the hydrophobic C-terminus of recombinant PH20 enzyme (column 86, Example 4, lines 7 and 18-20). Bookbinder teaches that the truncation may occur at residues P478, Q479, 1480, F481, Y482 (column 87, lines 14-15), N483 (column 86, line 64).Thus, Bookbinder teaches a fragment of the PH20 enzyme. One of ordinary skill in the art would have been motivated before the effective filing date of the claimed invention to use the truncated recombinant PH20 enzyme taught by Bookbinder in the combination of hyaluronidase enzyme (Bookbinder) and telomerase inhibitor (claims 1-39 of ‘778) discussed above in order to improve the solubility of the combination by removing the hydrophobic tail of hyaluronidase enzyme, as taught by Bookbinder.
Pertaining to claims 5-6 and 9, Bookbinder claim 1 recites “a hyaluronidase glycoprotein that consists of the sequence of amino acids set forth as amino acids 1-477, 36-477, 1-478, 36-478, 1-479, 36-479, 1-480, 36-480, 1-481, 36-481, 1-482, 36-482, 1-483 or 36-483 of 40 SEQ ID NO: 1,” wherein SEQ ID NO: 1 is 100% identical to the instant SEQ ID NO: 1, which represents the amino acid sequence of PH20. Thus, Bookbinder teaches N-terminal truncations of PH20 with a cleavage position before amino acid residue L36 and specifically teaches the PH20 fragment of 36-482. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the N-terminal truncations of PH20 taught by Bookbinder in the combination of claims 1-39 of ‘778 and Bookbinder. One of ordinary skill would have recognized that the N-terminal leader sequence would not have been required for the enzymatic activity of the PH20 enzyme because the leader sequence would have been removed during cellular production prior to purification, as taught by Bookbinder (Example 9, Purification of sHASEGP, column 93, lines 4-6).
Pertaining to claims 12-13, Bookbinder teaches an embodiment in which a hyaluronidase domain of a sHASEGP polypeptide, or a catalytically active portion thereof, does not include the entire sequence of amino acids set forth in SEQ ID NO: 1 but is at least 90% or 95% identical to SEQ ID NO: 1 (column 6, lines 25-29), wherein SEQ ID NO: 1 of Bookbinder is identical to the instant SEQ ID NO: 1 (the amino acid sequence of wild-type PH20).
Regarding claim 14, Bookbinder teaches unit dosage forms of a hyaluronidase enzyme, such as 1 to 5,000 Units of the enzyme in a small volume (column 59, lines 31-33) that are suitable for administration to a human (column 59, lines 9-12). 1 to 5,000 Units of a hyaluronidase enzyme overlaps with 100 U to 50,000 U. Bookbinder also teaches that the unit dosage (1 to 5,000 units of the enzyme) can be prepackaged in a syringe for use, such as after viscoelastic injection (column 59, lines 34-35), which is a form of subcutaneous injection. It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine a unit dosage of a hyaluronidase enzyme at a known and tolerated dosage acceptable for subcutaneous administration in a human with the telomerase inhibitor of Stuart in order to facilitate diffusion of the telomerase inhibitor, as discussed above. One of ordinary skill would have had a reasonable expectation of success given that the dosage of hyaluronidase enzyme taught by Bookbinder was formulated for subcutaneous administration.
Pertaining to claim 15, claims 1-39 of ‘778 do not recite and Bookbinder does not teach that the composition further comprises a pharmaceutically acceptable carrier.
Stuart teaches that the telomerase inhibitor is administered with a pharmaceutically acceptable excipient (column 4, lines 34-36).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to apply Stuart’s teaching regarding including a pharmaceutically acceptable excipient to the composition of claims 1-39 of ‘778 modified by Bookbinder, Stuart, and Frost. The person of ordinary skill in the art would have been motivated to do so and had a reasonable expectation of success because both claims 1-39 of ‘778 and Stuart’s teachings are drawn to a method of cancer treatment comprising administering a telomerase inhibitor (see Stuart claim 1 and claims 1-39 of ‘778).
Pertaining to claims 16-17, claims 1-39 of ‘778 do not recite that the composition comprising a telomerase inhibitor further comprises polysaccharides.
Stuart teaches that the telomerase inhibitor is administered as an aqueous solution with dissolution enhancers including 10% dextrose (a saccharide). A 10% dextrose solution is approximately 555 mM of saccharide, which is slightly above the claimed range of 10 mM to 500 mM. Therefore, a prima facie case of obviousness exists. See MPEP 2144.05.
Pertaining to claim 21, claims 1-39 of ‘778 d not recite that the composition comprising a telomerase inhibitor further comprises a buffer.
Stuart teaches that the telomerase inhibitor is administered with a buffer (column 33, lines 7-8).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to apply Stuart’s teaching regarding including saccharides and a buffer to the composition of claims 1-39 of ‘778 modified by Stuart, Bookbinder, Frost, and Soane. The person of ordinary skill in the art would have been motivated to do so and had a reasonable expectation of success because both claims 1-39 of ‘778 and Stuart’s teachings were drawn to a method of cancer treatment comprising administering a telomerase inhibitor (see Stuart claim 1 and claims 1-39 of ‘778).
Pertaining to claim 20, Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27). The concentration of histidine in the buffer is also 50 mM based on the 1:1 stoichiometry of histidine to hydrochloride. 50 mM is within the claimed range of from 1 mM to 100 mM.
Pertaining to claims 22-23, Bookbinder teaches that sHASEGP glycoproteins (hyaluronidase enzymes) are neutral active in vitro at pH between 5 and 8 under conditions of salt less than 150 mM and buffering strength less than 50 mM (column 25, lines 57-61). A buffering strength less than 50 mM overlaps with the claimed range of 1 to 100 mM. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to formulate a composition comprising both rHuPH20 and a telomerase inhibitor at acidic pH 5 to 8 in order to maintain the activity of the hyaluronidase enzyme. pH 5 to 8 overlaps with the claimed range of pH 3.0 to 9.0.
Regarding claim 30, claims 1-39 of ‘778 do not recite a dosage of 17.0 mg/kg to 20.0 mg/kg.
Regarding claim 31, claims 1-39 of ‘778 do not recite the claimed telomerase inhibitor dosages (e.g. 1500 mg to about 1600 mg).
Rather, claims 16 and 37 of ‘778 recite a dosage of 7.5-10 mg/kg for intravenous administration.
Stuart teaches that telomerase inhibitor compounds are effective over a wide dosage range and are generally administered in a therapeutically effective amount (Stuart, lines 32-34 of column 23). Stuart teaches: “It will be understood, however, that the amount of the telomerase inhibitor compounds actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms and the like” (Stuart, lines 32-41 of column 23).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the dosage of imetelstat in the composition of claims 1-39 of ‘778 modified by Bookbinder, Stuart, and Frost based on the variables taught by Stuart and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
Regarding claim 32, claims 1-39 of ‘778 do not recite that the composition is lyophilized.
In lines 45-46 and 65-66 of column 22, Stuart teaches that the active ingredient (telomerase inhibitor) may be lyophilized. Similarly, Bookbinder teaches that sHASEGP (a hyaluronidase enzyme) may be prepared as a lyophilized powder (Bookbinder, column 65, lines 31-32). Since both the telomerase inhibitor and the hyaluronidase enzyme may be prepared in lyophilized forms, it would have been obvious to one of ordinary skill in the art to formulate a composition comprising both components in lyophilized form.
Regarding claim 138, claims 1-39 of ‘778 do not recite that the telomerase inhibitor dosage is about 1500 mg to 2500 mg.
Stuart teaches that telomerase inhibitor compounds are effective over a wide dosage range and are generally administered in a therapeutically effective amount (Stuart, lines 32-34 of column 23). Stuart teaches: “It will be understood, however, that the amount of the telomerase inhibitor compounds actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms and the like” (Stuart, lines 32-41 of column 23). Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of imetelstat in the composition of claims 1-39 of ‘778 modified by Bookbinder based on the variables taught by Stuart and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
Claim 10 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-39 of U.S. Patent No. 12,171,778 (hereafter ‘778) in view of Bookbinder, Stuart, Frost, and Soane and as evidenced by Hanczyc and Centers for Disease Control, as applied to claims 1, 4-9, 12-17, 20-23, 30-32, and 138 above, further in view of Pecceu et al. (Genes Vol. 97, 1991, pp. 23-258).
See discussion of claims 1-39 of ‘778, Bookbinder, Stuart, Frost, and Soane above, which is incorporated into this rejection as well. Bookbinder teaches enhanced mammalian expression systems using signal leaders capable of efficient secretion of sHASEGP (column 5, lines 51-53).
Claims 1-39 of ‘778 do not recite that the N-terminus of the PH20 fragment comprises a human growth hormone-derived signal peptide.
Pecceu teaches that human interleukin 1β fused to the human growth hormone signal peptide is secreted by Chinese hamster ovary cells (Title). The sequence of the human growth hormone signal peptide is given in Figure 1B and is identical to SEQ ID NO: 3 of the instant application. Fig. 2 demonstrates the signal peptide nucleotide sequence is fused to the N-terminus of the gene.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to further modify the PH20 enzyme fragment in the composition of claims 1-39 of ‘778 modified by Bookbinder, Stuart, and Frost such that the enzyme could be produced in a mammalian expression system. One skilled in the art would have recognized that the secretion of the PH20 enzyme fragment would have required a signal peptide recognized by the expression system. One of ordinary skill would have been motivated to use the human growth factor-derived signal peptide taught by Pecceu because of its demonstrated success in recombinant protein expression by Chinese hamster ovary cells.
Claims 70 and 102 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-39 of U.S. Patent No. 12,171,778 (‘778) in view of Bookbinder, Stuart, and Soane and as evidenced by Hanczyc and Centers for Disease Control.
See discussion of claims 1-39 of ‘778, Bookbinder, and Stuart above, which are incorporated into this rejection as well.
Claims 1-39 of ‘778 do not recite and Bookbinder, Stuart, and Frost do not teach that the composition further comprises methionine or histidine.
Soane teaches the use of 50 mM histidine hydrochloride as a buffer in the viscosity measurements of formulations containing excipient compounds (paragraph 115, Example 1, line 27). The concentration of histidine in the buffer is also 50 mM based on the 1:1 stoichiometry of histidine to hydrochloride. The adjusted pH of the buffered formulations is 6.0 (paragraph 115, line 30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to buffer the formulation of claims 1-39 of ‘778 modified by Bookbinder, Stuart, and Frost using the histidine hydrochloride buffer taught by Soane. One of ordinary skill in the art would have been motivated to use a slightly acidic buffer system (such as pH 6.0) based on the activity of the hyaluronidase enzyme, which has an optimal pH at acidic to neutral conditions (Bookbinder column 25, lines 57-61).
Pertaining to claim 70, claims 1-39 of ‘778 do not recite that the composition is in unit dosage form.
Stuart teaches that a telomerase inhibitor composition may be formulated in a unit dosage form (column 22, lines 48-49 and column 23, lines 19-20). Bookbinder teaches that sHASEGP polypeptides (human hyaluronidase enzymes) may be formulated in unit dosage forms (column 58, lines 59 and 67 and column 59, line 1). It would have been obvious to formulate the composition of claims 1-39 of ‘778 modified by Stuart and Bookbinder in unit dosage form comprising telomerase inhibitor imetelstat and an effective amount of the hyaluronidase enzyme rHuPH20 to enhance the systemic distribution of imetelstat. One of ordinary skill in the art would have recognized the benefit of formulating the composition in a unit dosage form for ease of administration to the subject.
Regarding the amount of telomerase inhibitor in the composition in unit dosage form, claims 16 and 37 of ‘778 recite a dosage of 7.5-10 mg/kg for intravenous administration.
Stuart teaches that telomerase inhibitor compounds are effective over a wide dosage range and are generally administered in a therapeutically effective amount (Stuart, lines 32-34 of column 23). Stuart teaches: “It will be understood, however, that the amount of the telomerase inhibitor compounds actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms and the like” (Stuart, lines 32-41 of column 23).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the dosage of imetelstat in the composition of claims 1-39 of ‘778 modified by Bookbinder based on the variables taught by Stuart and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
Regarding claim 102, claims 1-39 of ‘778 do not recite that the composition is in a kit.
It would have been obvious to formulate the composition of claims 1-39 of ‘778 modified by Stuart and Bookbinder in a kit comprising telomerase inhibitor imetelstat and an effective amount of the hyaluronidase enzyme rHuPH20 to enhance the systemic distribution of imetelstat. One of ordinary skill in the art would have recognized the benefit of formulating the composition in a kit for the ease of retail to the customer (e.g. a medical clinic).
Regarding the amount of telomerase inhibitor in the composition in the kit, claims 16 and 37 of ‘778 recite a dosage of 7.5-10 mg/kg for intravenous administration.
Stuart teaches that telomerase inhibitor compounds are effective over a wide dosage range and are generally administered in a therapeutically effective amount (Stuart, lines 32-34 of column 23). Stuart teaches: “It will be understood, however, that the amount of the telomerase inhibitor compounds actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms and the like” (Stuart, lines 32-41 of column 23).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the dosage of imetelstat in the composition of claims 1-39 of ‘778 modified by Bookbinder based on the variables taught by Stuart and the person of ordinary skill in the art would have had a reasonable expectation of success in such routine optimization.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/CANDICE LEE SWIFT/Examiner, Art Unit 1657
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