DETAILED ACTION
Examiner acknowledges receipt of the reply filed 4/23/2026, in response to the restriction requirement mailed 02/25/2026.
Claims 1-26 are pending. Claims 7, 9-10, and 21 are withdrawn from further consideration for the reasons set forth below.
Claims 1-6, 8, 11-20, and 22-26 are being examined on the merits in this office action.
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The filing receipt dated 06/24/2025 provides the following:
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99
626
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Greyscale
Election/Restrictions
Applicant’s election of the following species without traverse in the reply filed on 4/23/2026 is acknowledged.
Disease to be treat: NAFLD, NASH
Long-acting growth hormone- formula c-ii, as-filed specification at p 90, lonapegsomatropin (Skytrofa)
Traversal between NAFLD and NASH is acknowledged (reply filed 4/23/2026 at p 1). Rejoinder of species- as limited to NAFLD and NASH - is acknowledged. NASH is rejoined herein.
Claims 1-6, 8, 11-20, and 22-26 read on the elected species.
Claims 7, 9-10, and 21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/23/2026.
Specification
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
The use of the term TWEEN®, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. See as-filed specification at p. 19, l. 24.
Sequence Interpretation
The Office interprets claims comprising SEQ ID NOs: in the following manner: “comprising a sequence of SEQ ID NO: 1” requires only a 2mer (dipeptide, consecutive 2 amino acids) of SEQ ID NO: 1, “comprising the sequence of SEQ ID NO: 1” requires the full-length sequence with 100% identity to SEQ ID NO: 1 with any N-/C-terminal additions or any 5’/3’ additions, “consisting of SEQ ID NO: 1” requires the full-length sequence with 100% identity to SEQ ID NO: 1 and the same length as SEQ ID NO: 1, “an amino acid selected from the group consisting of SEQ ID NOs: 1-3” requires only a 2mer (dipeptide, consecutive 2 amino acids) or more, and “the amino acid selected from the group consisting of SEQ ID NOs: 1-3” requires the full length sequence that is nothing less and nothing more.
Claim Objections
Claims 1, 3, 11, 12, and 19 are objected to because of the following informalities:
Claim 1 should be amended to recite “to the patient in need thereof”.
Claim 3 should be amended to depend from claim 2, not claim 1. Claim 2 recites wherein the inflammation-induced disease is NAFLD. Claim 3 recite NASH. As noted in Applicant’s reply filed 4/23/2026 at page 1, NASH is a subtype of NAFLD. Thus, claim 3 further limits claim 2.
Claim 11 should be amended to recite “long-acting GH triggers [[the]] re- balancing”.
Claim 12 should be amended to recite “from the group consisting of cytokines, chemokines, markers, and histological markers”.
Claim 19 should be amended to recite “wherein -D comprises the amino acid sequence .
Appropriate correction is required.
Examiner recommends that claim 16 be amended to remove the second recitation of “(C-ii)” under the recited structure, as this is redundant. The claim should further be amended to rephrase: -D is a hGH moiety connected to the rest of the molecule through the nitrogen of an amine functional group of -D;. specifically, amended to remove “the” and that the -D compound comprises a functional amine group that forms a covalent bond.
Claim 20 could be amended to recite that the amine functional group is a lysine side chain (or similar language).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 8, 11, 16, 19, 20, 22, and 23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 8 recites the limitation “the bond”. There is insufficient antecedent basis for this limitation in the claims. Claim 8 depends from claim 4. Claim 4 recites “covalently conjugated” but does not recite a bond. Examiner recommends that claim 4 be amended to refer to a covalent bond. Claim 7 could then be amended to recite “the covalent bond”.
Claim 11 recites the limitation “the re-balancing”. There is insufficient antecedent basis for this limitation in the claims.
Claim 16 recites the limitations "the rest" and “the molecule”. There is insufficient antecedent basis for these limitations in the claim.
Claims 19 and 20 depend from claim 12. Claims 19 and 20 recite the limitation “-D”. There is insufficient antecedent basis for the limitations in the claims. Claim 16, not claim 12, provides a chemical structure that includes the variable position “-D”. To overcome this rejection, revise claim dependency of claims 19 and 20 to properly depend from claim 16.
Claims 22 and 23 recite the limitations “the treatment” and “the dose”. There is insufficient antecedent basis for these limitations in the claims. Claims 22 and 23 depend from claim 1. Claim 1 refers to “treating” and “a pharmaceutically effective amount”.
Claim 23 further recites the limitation “the macrophage phenotype change”. There is insufficient antecedent basis for this limitation in the claims.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-6, 8, 11-20, and 22-26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The courts have stated:
“To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP §2163.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co., the court stated:
“A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials. Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284-85 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus. . . ."). Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representative, the Courts have indicated what do not constitute a representative number species to adequately describe a broad generic. In Gosteli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gosteli, 872 F.2d at 1012, 10 USPQ2d at 1618.
For written description, the analysis considers
(a) Actual reduction to practice,
(b) Disclosure of drawing or structural chemical formulas,
(c) Sufficient relevant identifying characteristic in the way of complete/partial structure or physical and/or chemical properties, functional characteristics when coupled with known or disclosed and
(d) Representative number of examples.
In the instant case, the claims are drawn to a method of treating an inflammation-induced disease in a patient, wherein the method comprises a step of administering a pharmaceutically effective amount of a long-acting growth hormone (GH) to the patient. Claims 2 and 3 recite that the inflammation-induced disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), respectively.
The specification does not expressly define the term “treating”. The specification does not expressly define the term “inflammation-induced disease”.
The specification states, in part:
As used herein, the term “growth hormone” or “GH” refers to all growth hormone protein sequences, preferably from mammalian species, more preferably from human and mammalian species, more preferably from human and murine species, and includes in certain embodiments also their variants, analogs, orthologs, homologs, and derivatives and fragments thereof. Growth hormone is characterized by promoting growth in the growing phase and maintains normal body composition, anabolism, and lipid metabolism. In certain embodiments the term “human growth hormone” or “hGH” refers to the hGH polypeptide of SEQ ID NO:1 and includes its variants, homologs and derivatives exhibiting essentially the same biological activity, i.e. promoting growth in the growing phase and maintaining normal body composition, anabolism, and lipid metabolism. In certain embodiments the term “hGH” refers to the sequence of SEQ ID NO:1.
As used herein, the term “GH variant” refers to a GH protein from the same species that differs from a reference GH protein, such as from the hGH of SEQ ID NO:1. In certain embodiments, such GH variants are at least 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to a reference GH, such as the hGH of SEQ ID NO:1. ...
As used herein, the term “GH analog” refers to GH of different and unrelated organisms which perform the same functions in each organism, but which did not originate from an ancestral structure that the organisms' ancestors had in common. ...
As used herein the term “GH ortholog” refers to GH within two different species which sequences are related to each other via a common homologous GH in an ancestral species, but which have evolved to become different from each other.
As used herein, the term “GH homolog” refers to GH of different organisms which perform the same functions in each organism, and which originate from an ancestral structure that the organisms' ancestors had in common. In other words, homologous GH proteins are proteins with quite similar amino acid sequences that perform the same biological activity, namely promoting growth in the growing phase and maintaining normal body composition, anabolism, and lipid metabolism. …
Specification at pp 3-5, not including SEQ ID NO:1 amino acid sequence. The specification further states at p. 6:
As used herein the term “long-acting growth hormone” refers to a compound which comprises GH either in crystallized form or wherein the GH is embedded, fused or covalently conjugated to at least one other chemical compound or moiety, such as for example a polymer, fatty acid or fatty acid variant moiety, and has an increased clearance half-life in a patient's body compared to unmodified GH, such as a clearance half-life that is at least 10-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 100-fold or at least 200-fold higher than the clearance half-life of the corresponding unmodified GH. In certain embodiments the GH is hGH, such as the hGH of SEQ ID NO:1.
(a) Actual reduction to practice/ (b) disclosure of drawing or structural chemical formulas:
Example 1 discloses synthesis of lonapegsomatropin (compound 1), disclosed in Example 2 of WO2016/079114. Lonapegsomatropin comprises instant SEQ ID NO:1. Example 2 discloses treatment of NASH mice with lonapegsomatropin (compound 1). Mice exhibited a decrease in plasma markers of liver damage (ALT and AST), a decrease in liver triglycerides, decrease in steatosis, a decrease in cholesterol, and an improvement in liver inflammation (e.g., recruitment of macrophages, and downregulation of fibrosis gene markers).
The specification is limited to disclosing a single, full-length peptide of SEQ ID NO:1, and a single embodiment of a “long-acting growth hormone”, lonapegsomatropin. It is further noted that specification is limited to treating one disease within the scope of “inflammation-induced disease”, NASH. The specification did not reduce to practice any peptide other than full-length polypeptide with 100% to SEQ ID NO:1.
(c) Sufficient relevant identifying characteristic in the way of complete/partial structure or physical and/or chemical properties, functional characteristics when coupled with known or disclosed: and (d) Representative number of examples:
Given the broadest reasonable claim interpretation, the claims encompass treating an inflammation-induced disease (undefined disease) in a patient (reads on mammals, etc) comprising administering a pharmaceutically effective amount of a long-acting growth hormone (GH) of variable sequence, including but not limited to, a peptide having at least 70% sequence identity [variants] to instant SEQ ID NO:1, wherein the growth hormone is embedded/fused/covalently attached to a “chemical compound or moiety” (e.g., any polymer, fatty acid or fatty acid variant moiety).
Furthermore, the present application is attempting to patent what has not yet been invented and the fact that one of skill in the art can test for the effect used to determine the compounds does not necessarily confer sufficient written description. The claimed polypeptide sequence would entail testing limitless potential peptides and proteins, and one of skill in the art could afterwards still be faced with no hits with the desired functionality.
The specification is limited to a peptide having 100% identity with instant SEQ ID NO: 1. SEQ ID NO:1 is 191 amino acids in length. 70% sequence identity to SEQ ID NO:1 allows for up to 58 amino acid changes (e.g., substitution, insertion, deletion, or any combination thereof). There are 20 naturally occurring amino acids. Thus, there are 5820 (or 1.85 x1035) potential polypeptides within the instant claim scope peptides having at least 70% identity to SEQ ID NO:1. The actual number of variants is much higher when one considers non-naturally occurring amino acids.
In addition, it is well known in the peptide/protein art that even single amino acid changes or differences in the amino acid sequence of a protein can have dramatic effects on the protein’s function. As an example of the unpredictable effects of mutations on protein function, Drumm et al (Annu. Rev. Pathol. Mech. Dis., 2012, 7, pages 267-282) teach cystic fibrosis is an autosomal recessive disorder caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, for example, page 268, Section “CYSTIC FIBROSIS”. Drumm et al further teach several mutations can cause cystic fibrosis, including two mutations G551D and G551S; and clinical consequences are quite different for these two changes, as the G551D variant has virtually no detectable activity, and consequently a classic, severe phenotype is associated; G551S, however, has reduced but clearly detectable function and is associated with a much milder presentation of CF, for example page 269, left column, the last paragraph. Drumm et al also teach that in the most common cystic fibrosis mutation ΔF508 (the absence of amino acid 508 of the normally 1,480-amino acid protein) gives rise to the cystic fibrosis phenotype, for example, page 268, right column, the 2nd paragraph. Thus, even the substitution or deletion of a single amino acid can have dramatic and unpredictable effects on the function of the protein. The unpredictability of the effect of amino acid substitution on the function and/or property of peptide/protein is further confirmed and discussed in Yampolsky et al (Genetics, 2005, 170, pages 1459-1472). Yampolsky et al teach even conservative substitution can significantly affect the function of the protein/peptide, for example, page 1465, Table 3. Although the disclosures of Drumm et al and Yampolsky et al are directed to peptides other than those used in matrix binding selectivity of a body fluid component, they illustrate the inherent unpredictability with respect to the biological activity of a given protein/peptide after even minor changes to the primary amino acid sequence.
Therefore, based on the state of art, a person of ordinary skill in the art would not be able to determine what structural feature is required for the claimed polypeptide sequence to have the functional characteristics of having functionality as a growth hormone and utility in treating an inflammation-induced disease.
As stated earlier, the MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic. It must not be forgotten that the MPEP states that if a biomolecule is described only by a functional characteristic and/or a functional/structural characteristic without any disclosed correlation between function and structure of the biomolecule beyond the examples presented, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed biomolecule.” MPEP 2163. Here, though the claims may recite some functional characteristics, and even some generic structural features and several distinct species are given (e.g. long-actional GH structure of claim 16 and growth hormone of SEQ ID NO:1, claim 19), the claims lack written description because there is no disclosure of a correlation between function and structure of the recited at growth hormone sequence other than full-length protein, and “chemical compound or moiety” that give rise to form the claimed long-acting GH. Accordingly, there are not only many distinct components (GH proteins/variants/homologs/orthologs, and chemical compound or moieties to mediate “long-acting”), there are also numerous combinations of components that fall within the instant claim scope to give rise to a claimed long-acting GH. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate").
The skilled artisan cannot extrapolate to the myriad of long-acting growth hormones that fall within the instant claim scope based on the limited guidance in the specification. It is noted that no one long-acting GH was reduced to practice, lonapegsomatropin.
Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Claims 1-6, 8, 11-20, and 22-26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) with lonapegsomatropin, does not reasonably provide enablement for treating all diseases that fall under the scope of “inflammation-induced diseases” much less with growth hormone polypeptides (and variants, analogs, orthologs, homologs thereof) that fall within the scope of “long-acting growth hormone”. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation.
(1) The nature of the invention and (5) The breadth of the claims:
The invention is drawn to a method of treating an inflammation-induced disease in a patient, wherein the method comprises a step of administering a pharmaceutically effective amount of a long-acting growth hormone (GH) to the patient. Claims 2 and 3 recite that the inflammation-induced disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH), respectively.
The specification does not expressly define the term “treating”. The specification does not expressly define the term “inflammation-induced disease”.
The specification states that the long-acting growth hormone inhibits recruitment of inflammatory monocytes to the site of inflammation. Such site of inflammation is the liver, if the inflammation-induced disease is NAFLD, in particular NASH. The long-acting growth hormone leads to an increase in HLA-G in the liver, and results in an increase in IGF-1 levels. Administration of the long-acting growth hormone leads to a change in one or more markers of hepatic inflammation selected from the group consisting of cytokines, chemokines and other transcriptional and histological markers; e.g., an improvement of transcriptional or histological markers of fibrosis. The long-acting growth hormone leads to a reduction in steatosis, and a regeneration of the liver if the inflammation-induced disease is a disease of the liver (as-filed specification at p. 20).
The specification states:
As used herein, the term “growth hormone” or “GH” refers to all growth hormone protein sequences, preferably from mammalian species, more preferably from human and mammalian species, more preferably from human and murine species, and includes in certain embodiments also their variants, analogs, orthologs, homologs, and derivatives and fragments thereof. Growth hormone is characterized by promoting growth in the growing phase and maintains normal body composition, anabolism, and lipid metabolism. In certain embodiments the term “human growth hormone” or “hGH” refers to the hGH polypeptide of SEQ ID NO:1 and includes its variants, homologs and derivatives exhibiting essentially the same biological activity, i.e. promoting growth in the growing phase and maintaining normal body composition, anabolism, and lipid metabolism. In certain embodiments the term “hGH” refers to the sequence of SEQ ID NO:1.
As used herein, the term “GH variant” refers to a GH protein from the same species that differs from a reference GH protein, such as from the hGH of SEQ ID NO:1. In certain embodiments, such GH variants are at least 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to a reference GH, such as the hGH of SEQ ID NO:1. By a protein having an amino acid sequence at least, for example, 95% “identical” to a query amino acid sequence, it is intended that the amino acid sequence of the subject protein is identical to the query sequence except that the subject protein sequence may include up to five amino acid alterations per each 100 amino acids of the query amino acid sequence. These alterations of the reference sequence may occur at the amino (N-terminal) or carboxy terminal (C-terminal) positions of the reference amino acid sequence or anywhere between those terminal positions or in any combination thereof. These alterations of the reference sequence may either be interspersed among residues in the reference sequence or may be in one or more contiguous groups within the reference sequence. Such GH variants may be naturally occurring variants, such as naturally occurring allelic variants encoded by one of several alternate forms of a GH occupying a given locus on a chromosome or an organism, or isoforms encoded by naturally occurring splice variants originating from a single primary transcript. Alternatively, a GH variant may be a variant that is not known to occur naturally and that can be made mutagenesis techniques known in the art.
As used herein, the term “GH analog” refers to GH of different and unrelated organisms which perform the same functions in each organism, but which did not originate from an ancestral structure that the organisms' ancestors had in common. Instead, analogous GHs arose separately and then later evolved to perform the same or similar functions. In other words, analogous GH proteins are proteins with quite different amino acid sequences but that perform the same biological activity, namely promoting growth in the growing phase and maintaining normal body composition, anabolism, and lipid metabolism.
As used herein the term “GH ortholog” refers to GH within two different species which sequences are related to each other via a common homologous GH in an ancestral species, but which have evolved to become different from each other.
As used herein, the term “GH homolog” refers to GH of different organisms which perform the same functions in each organism, and which originate from an ancestral structure that the organisms' ancestors had in common. In other words, homologous GH proteins are proteins with quite similar amino acid sequences that perform the same biological activity, namely promoting growth in the growing phase and maintaining normal body composition, anabolism, and lipid metabolism. In certain embodiments such GH homologs may be defined as proteins exhibiting at least 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identity to a reference GH sequence, such as to the hGH of SEQ ID NO:1.
Specification at pp 3-5, not including SEQ ID NO:1 amino acid sequence. Emphasis added.
The specification further states at p. 6:
As used herein the term “long-acting growth hormone” refers to a compound which comprises GH either in crystallized form or wherein the GH is embedded, fused or covalently conjugated to at least one other chemical compound or moiety, such as for example a polymer, fatty acid or fatty acid variant moiety, and has an increased clearance half-life in a patient's body compared to unmodified GH, such as a clearance half-life that is at least 10-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 100-fold or at least 200-fold higher than the clearance half-life of the corresponding unmodified GH. In certain embodiments the GH is hGH, such as the hGH of SEQ ID NO:1.
Thus, the claims encompass treating an inflammation-induced disease (undefined disease) in a patient (reads on mammals, etc) comprising administering a pharmaceutically effective amount of a long-acting growth hormone (GH) of variable sequence, including but not limited to, a peptide having at least 40% sequence identity [homologs] to instant SEQ ID NO:1, wherein the growth hormone is embedded/fused/covalently attached to a chemical compound or moiety.
(2) The state of the prior art: the following reflects just a few disorders that falls within the claim scope of “inflammation-induced diseases”.
The Merck manual indicates that there are plethora of inflammatory disorders known, for example, Pelvic Inflammatory Disease, Temporomandibular Disorders, and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), to name just a few (see Merck manual, Inflammatory Disorders enclosed). Additionally, the Merck manual indicates that there are numerous numbers of types of dermatitis, for example, contact dermatitis, stasis dermatitis, perioral dermatitis, atopic dermatitis (Eczema), to name just a few (see Merck manual, Dermatitis enclosed). Additionally, the Merck manual indicates that there are plethora of inflammations (see Merck manual, Inflammation enclosed).
Cornier et al. (Endo. Rev. 29:777-822 (2008)) is a review article discussing metabolic syndrome. Metabolic syndrome (MetS) is a clustering of components that reflect over-nutrition, sedentary lifestyles, and resultant excess adiposity. The MetS includes the clustering of abdominal obesity, insulin resistance, dyslipidemia, and elevated blood pressure and is associated with other comorbidities including the prothrombotic state, proinflammatory state, nonalcoholic fatty liver disease, and reproductive disorders (abstract). MetS is not a single disease. Id. Treatment of MetS involves lifestyle modification (diet, exercise) and treatment for underlying/associated conditions, e.g., diabetes, weight loss, high blood pressure, dyslipidemia, (pp. 797-803).
With regard to Multiple Sclerosis, another inflammatory disease, although there have been substantial progress reported in the scientific literature about the multiple etiologies of multiple sclerosis, including genetic makeup and environmental factors, multiple sclerosis remains a “difficult disease for which solutions seem attainable yet remain elusive” (Compston et al., The Lancet 359:1221-1231 (2002) at p. 1221, para. 1 and p. 1224, para. 6 – p. 1225, para. 2). See also p. 1226-1228 discussing the various treatments of MS with β-interferons and synthetic amino acid polypeptides, corticosteroids, etc.
Rheumatoid arthritis (RA; accessed 10/24/2017 at URL merckmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders (pp. 1-26) is a chronic systemic autoimmune disease that primarily involves the joints (abstract). RA causes damage mediated by cytokines, chemokines, and metalloproteases. Characteristically, peripheral joints (e.g., wrists, metacarpophalangeal joints) are symmetrically inflamed, leading to progressive destruction of articular structures, usually accompanied by systemic symptoms. Id. Treatment of RA involves supportive measures (nutrition, rest, analgesics), drugs that modify disease progression (e.g., TNF-alpha antagonists, IL-1 receptor antagonists, IL-6 blockers, B-cell depleters, T-cell costimulatory molecules, and Janus kinase (JAK) inhibitors, and corticosteroids), and surgery (pp. 14-25).
The art recognizes that there are countless different inflammatory conditions, disorders and diseases, but does not provide how to determine the individuals who are susceptible to these inflammation, inflammatory disorders, and disorders characterized by inflammation.
Schaffler et al. (Nat. Rev. Gastroenterol. Hepat. 2:273-280 (2005)), is a review article discussing the role of visceral adipose tissue in fatty liver and nonalcoholic steatohepatitis (abstract). Nonalcoholic fatty liver disease comprises hepatic steatosis (fatty liver disease), nonalcoholic steatohepatitis (NASH), fibrosis and liver cirrhosis (p. 273, para. 1). There is a positive correlation between hepatic insulin resistance and liver fat content, and most obese patients have evidence of fatty liver or even NASH, a condition in which fat deposition in the liver is accompanied by fibrosis and necroinflammation (Figure 1). The high extent of lipid deposition and lipolysis in visceral adipose tissue (VAT) leads to an increased flux of free fatty acids (FFAs) to the liver via the portal vein. Id. at para. 2. FFAs are stored as triglycerides in the cytoplasm and are used for the assembly of the main precursor of LDL, VLDL, in the endo plasmatic reticulum. Id. at para. 2. The chronic hepatic lipid overload results in lipid storage and insulin resistance. Id. High levels of glucose activate the transcription factor carbohydrate responsive element binding protein, inducing the synthesis of FFAs by the liver leading to development of fatty liver (Figure 2). There is growing evidence that obesity and especially excessive visceral fat disturb the secretion of adipocytokines - secretory products derived from adipose tissue- thus contributing to the pathologic features of NASH (Table 1).
Nonalcoholic fatty liver disease (NAFLD) is associated with hepatic steatosis (retention of lipids in liver cells) (Chalasani et al., Hepatology 55:2005-2023 (2012))- p. 2005). In the majority of patients, NAFLD is associated with metabolic risk factors such as obesity, diabetes mellitus, and dyslipidemia. NAFLD is histologically further categorized into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) (Table 3). Treatment of NAFLD involves lifestyle changes (diet and exercise), insulin sensitizing agents, bariatric surgery, statins, vitamin E, and thiazolidinediones (pp. 2011-2014).
Nonalcoholic steatohepatitis (NASH) (Merck Manual, accessed 7/29/2016 at URL merckmanual.com, pp. 1-3) teaches that the pathophysiology of Nonalcoholic steatohepatitis (NASH) involves fat accumulation (steatosis), inflammation, and, variably, fibrosis. Steatosis results from hepatic triglyceride accumulation. Risk factors such as obesity, type 2 diabetes mellitus, or dyslipidemia and in patients with unexplained laboratory abnormalities suggesting liver disease. The most common laboratory abnormalities are elevations in aminotransferase levels. Prognosis is hard to predict. Most patients do not develop hepatic insufficiency or cirrhosis. However, some drugs (e.g., cytotoxic drugs) and metabolic disorders are associated with acceleration of NASH. Prognosis is often good unless complications develop. Treatment involves elimination of causes and control of risk factors. The only widely accepted treatment goal is to eliminate potential causes and risk factors, e.g., discontinuation of drugs or toxins, weight loss, and treatment for dyslipidemia or treatment for hyperglycemia. Several drugs, e.g., metformin and betaine have not been proved effective.
(3) The relative skill of those in the art:
MPEP 2141.03 states (in part)” A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR International Co. v. Teleflex Inc., 127 S.Ct. 1727, 167 LEd2d 705, 82 USPQ2d 1385, 1397 (2007). “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. At 1396, 82 USPQ2d at 1396. The “hypothetical person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988) (disagreeing with the examiner’s definition of one of ordinary skill in the art (i.e. a doctorate level engineer or scientist working at least 40 hours per week in semiconductor research or development), and finding that the hypothetical person is not definable by way of credentials, and that the evidence in the application did not support the conclusion that such a person would require a doctorate or equivalent knowledge in science or engineering). In the instant case, the skill in the art high with respect to physicians and scientists. The level of skill in the art (physicians and scientists) would be high.
(4) The predictability or unpredictability of the art:
It is noted that pharmaceutical and biological art is generally unpredictable, requiring each embodiment to be individually assessed for physiological activity. Given this fact, historically the development of new drugs has been difficult and time- consuming. Adding to the unpredictability is that many treatment options may show promise in animal models, but may fail to show therapeutic improvement in clinical trials. There is no absolute predictability, even in view of the high level of skill in the art. The invention is directed toward medicine and is therefore physiological in nature. It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved," and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The claims don’t identify the type of inflammation or disease/disorder or condition induced by inflammation. Applicant has not shown who will be susceptible to inflammation, inflammatory disorders, and disorder or condition induced by inflammation. There are too many variables between the patient populations, thus, it clearly shows the unpredictability of the art.
There is no absolute predictability, even in view of the high level of skill in the art.
(6) The amount of direction or guidance presented and (7) The presence or absence of working examples:
Example 1 discloses synthesis of lonapegsomatropin (compound 1), disclosed in Example 2 of WO2016/079114. Lonapegsomatropin comprises instant SEQ ID NO:1. Example 2 discloses treatment of DIO-NASH mice with lonapegsomatropin (compound 1). Mice exhibited a decrease in plasma markers of liver damage (ALT and AST), a decrease in liver triglycerides, decrease in steatosis, a decrease in cholesterol, and an improvement in liver inflammation (e.g., recruitment of macrophages, and downregulation of fibrosis gene markers).
There is no specific guidance as to treatment of other inflammation-induced diseases, beyond NASH.
The specification has not provided guidance as to other types of inflammatory disorders/diseases. There is no clear guidance as to the patient population, since not all people suffer from the same disorder, condition or disease, and the amount of long-action growth hormone necessary to treat ALL inflammation and inflammatory disorders/diseases is unclear from the specification. Since the art recognizes that there are countless different inflammation and inflammatory disorders/diseases, but does not provide how to determine the individuals who are susceptible to these disorder, condition or disease list provided by the Merck manual, more guidance is necessary.
(8) The quantity of experimentation necessary:
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here.
It is further noted that the specification is limited to a single form of a “long-acting growth hormone”- comprising a single protein sequence, and chemical moiety- lonapegsomatropin- and treatment of NASH as the singular embodiment of a “inflammation-induced disease”.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries 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.
Claim(s) 1-6, 8, 14, 15, and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Takahashi (Int J Mol Sci 18:1447 (2017)- cited in IDS filed 4/15/2024), and in further view of Rau et al (U.S. 2011/0112021- cited in IDS filed 4/15/2024; issued as Pat No 9272048).
Takahashi teaches administering growth hormone for treating NASH or cirrhosis (e.g., abstract, p. 8). GH profoundly reduces visceral fat, which plays an important role in the development of NAFLD. Furthermore, GH directly reduces lipogenesis in the hepatocytes (e.g., abstract). Takahashi teaches owing to the increasing prevalence of obesity and type 2 diabetes (T2DM), non-alcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of chronic liver disease worldwide. NAFLD consists of non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), and encompasses liver conditions ranging from simple steatosis to cirrhosis (p. 1). GH replacement therapy drastically reversed NASH, concomitant with a decrease in inflammation and oxidative stress markers (p. 2).
Although Takahashi teaches a method of treating non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) comprising growth hormone, the reference does not explicitly teach a long-acting growth hormone.
Rau et al teach a chemically modified human Growth Hormone (rhGH) comprising a polyethylene glycol. The chemically modified protein has a longer lasting rhGH activity than that of the unmodified rhGH, enabling reduced dose and scheduling opportunities and the modified rhGH may not cause lipoatrophy (abstract). Rau et al state that by PEGylating rhGH, it may be possible to improve the characteristics of the molecule for medical use by increasing its in vivo half-life (hereby achieving reduced dosage or reduced frequency of dosing), improving its stability and decreasing its anti-genicity or a combination thereof (e.g., para [0010]). Long-acting GH compounds include
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wherein m is between 400-500 (e.g., claim 36).
It would have been obvious to one of ordinary skill in the art to administer a growth hormone (GH) to a patient with NAFLD or NASH in order to treat the liver disease, as taught by Takahashi. The skilled artisan would have been motivated to administer a long-acting growth hormone of Rau in a method of treating NAFLD or NASH. Rau et al taught that the GH prodrugs/long-acting GH allowed for a stable/longer lasting GH as compared to unmodified GH, improved pharmacokinetics (half-life and decreased antigenicity), and reduced frequency of GH dosing/administration. The U.S. Federal Circuit has explicitly stated that in order to make a prima facie case of obviousness, the suggestion and motivation to combine the references need not be explicitly stated in the text of the references. In DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641 (Fed. Cir. 2006), the Court writes, “the suggestion test is not a rigid categorical rule. The motivation need not be found in the references sought to be combined, but may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself. In re Dembiczak, 175 F.3d 994, 999 [50 USPQ2d 1614] (Fed. Cir. 1999). As we explained in Motorola, Inc. v. Interdigital Tech. Corp., 121 F.3d 1461, 1472 [43 USPQ2d 1481] (Fed. Cir. 1997), ‘there is no requirement that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.’” See Dystar at 1645. “Our suggestion test is in actuality quite flexible and not only permits, but requires, consideration of common knowledge and common sense.” See Dystar at 1650.
In this case, a method of treating NAFLD or NASH comprising administering GH was known in the art at the time of the invention (as taught by Takahashi). The skilled artisan would further have known of a long-acting/prodrug GH that allowed for stable/longer lasting GH as compared to unmodified GH, improved pharmacokinetics (half-life and decreased antigenicity), and reduced frequency of GH dosing/administration. Accordingly, the motivation to administer the long-acting GH of Rau can be found in the common knowledge of the art and common sense of its skilled practitioners. The skilled artisan would have had a reasonable expectation of success because growth hormone and long-acting GH both comprise growth hormone. See also In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious.”). There is no showing of art or record that the long-acting growth hormone of Kurpiers would be less effective than unmodified growth hormone.
Accordingly, claims 1-3 are rendered obvious.
Regarding claims 4-6, growth hormone is covalently conjugated to one or more chemical moiety, e.g., Peg-based (e.g., paras [0069]-[0073], Examples 1, 7-23, claims 1-4, 36). Regarding claim 8, the bond can be a reversible covalent bond (e.g., paras. [0087]). Regarding claim 14, Takahashi teaches that GH reduced steatosis (pp. 5-8, Fig 2). Regarding claim 15, Rau et al teach that the long-acting GH is administered to the patient once a week (e.g., paras [0036], Ex 26-27). Regarding claim 20, GH (-D variable) can be attached via nitrogen in a lysine side chain amine group (e.g., paras [0027], [0126]).
Claim(s) 1-6, 8, and 14-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Takahashi (Int J Mol Sci 18:1447 (2017)- cited in IDS filed 4/15/2024) and Rau et al (U.S. 2011/0112021- cited in IDS filed 4/15/2024; issued as Pat No 9272048), as applied to claims 1-6, 8, 14, 15, and 20 above, and further in view of Kurpiers et al (U.S. 2017/0354716; issued as Pat No 10799563).
The teachings of Takahashi and Rau et al are set forth above. The references do not explicitly teach the limitations of instant claims 16-19.
Kurpiers et al teach polymeric human growth hormone prodrug and dry, liquid and reconstituted pharmaceutical formulations comprising said prodrug (abstract). The polymeric human growth hormone prodrug allows for less frequent injection and sustained release formulations, and increased half-life (e.g., paras [0004]-[0010], [0034]-[0036], [0047], Ex 6). Example 2 discloses preparation of
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, wherein n is between 200 to 250. Examples 7 and 9 indicate improved pharmacokinetics of the claimed long acting growth hormone. Kurpiers teach a method of treating, controlling, delaying, or preventing in a mammalian patient in need of the treatment, control, delay, or prevention of at least one diseases which can be treated, controlled, delayed, or prevented with hGH, wherein the method comprises a step of administering to said patient a therapeutically effective amount of the prodrug (e.g., claims 1, 3, 4, 18).
It would have been obvious to one of ordinary skill in the art to substitute the long-acting growth hormone of Rau with the long-acting growth hormone of Kurpiers, for use in the method of treating a patient with NAFLD or NASH in order to treat the liver disease, as taught by Takahashi. A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the long-acting growth hormones because they are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”). It is further noted that Kurpiers synthesized the long-acting GH of Rau in Example 1, wherein n = 400-500 (Rau at eg claim 36). Example 2 disclosed the compound wherein n = 200-250 (n correlates with instant p1, p2, p3, and p4).
Accordingly, claim 16 is rendered obvious. Regarding claims 17 and 18, Kurpiers et al teach the long-acting GH compound
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wherein D is a hGH moiety connected to the rest of the molecule through an amine functional group; and p1, p2, p3, p4 are independently an integer ranging from 180 to 270, preferably from 200 to 250, even more preferably from 210 to 240 and most preferably from 220 to 240 (e.g., paras [0205]-[0208], Example 2, claim 4)). Regarding claim 19, SEQ ID NO:1 of Kurpiers et al has 100% identity with instant SEQ ID NO:1.
Accordingly, claims 1-6, 8, and 14-20 are rendered obvious in view of the teachings of the cited references.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6, 8, and 14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-37 of U.S. Patent No. 9272048 (hereinafter referred to as “the ‘048 patent”- cited in IDS filed 5/14/2024) in view of Takahashi (Int J Mol Sci 18:1447 (2017)- cited in IDS filed 4/15/2024).
The instant claims are drawn to a method of treating an inflammation-induced disease in a patient comprising administering a pharmaceutically effective amount of a long acting growth hormone to the patient.
The claims of the ‘048 patent are drawn to a pharmaceutical composition comprising suitable pharmaceutical excipients; and a human in vivo clinical effective amount of a recombinant human growth hormone (rhGH) PEGylated prodrug conjugate, wherein PEG is linked to rhGH via a self hydrolysable (autocleavage) transient linker from which the rhGH is released in its native form; wherein the prodrug conjugate has a GH activity which is less than 5% of the native growth hormone without PEG; and wherein the linker autohydrolysis rate of the prodrug conjugate is such that the in vivo half-life of the prodrug conjugate is from 10 hours to 600 hours; wherein the term in vivo half-life refers to the time interval in which 50% of the initial proportion of the growth hormone is released from the hGH PEGylated prodrug [reads on long-acting GH].
The claims of the ‘048 patent do not expressly teach a method of treating an inflammation-induced disease in a patient, e.g. NAFLD or NASH.
Takahashi teaches administering growth hormone for treating NASH or cirrhosis (e.g., abstract, p. 8). GH profoundly reduces visceral fat, which plays an important role in the development of NAFLD. Furthermore, GH directly reduces lipogenesis in the hepatocytes (e.g., abstract). Takahashi teaches owing to the increasing prevalence of obesity and type 2 diabetes (T2DM), non-alcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of chronic liver disease worldwide. NAFLD consists of non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), and encompasses liver conditions ranging from simple steatosis to cirrhosis (p. 1). GH replacement therapy drastically reversed NASH, concomitant with a decrease in inflammation and oxidative stress markers (p. 2).
It would have been obvious to one of ordinary skill in the art to administer a growth hormone (GH) to a patient with NAFLD or NASH in order to treat the liver disease, as taught by Takahashi. The skilled artisan would have been motivated to administer a long-acting growth hormone of the claims of the ‘048 patent in a method of treating NAFLD or NASH. The U.S. Federal Circuit has explicitly stated that in order to make a prima facie case of obviousness, the suggestion and motivation to combine the references need not be explicitly stated in the text of the references. In DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641 (Fed. Cir. 2006), the Court writes, “the suggestion test is not a rigid categorical rule. The motivation need not be found in the references sought to be combined, but may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself. In re Dembiczak, 175 F.3d 994, 999 [50 USPQ2d 1614] (Fed. Cir. 1999). As we explained in Motorola, Inc. v. Interdigital Tech. Corp., 121 F.3d 1461, 1472 [43 USPQ2d 1481] (Fed. Cir. 1997), ‘there is no requirement that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.’” See Dystar at 1645. “Our suggestion test is in actuality quite flexible and not only permits, but requires, consideration of common knowledge and common sense.” See Dystar at 1650. See also In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious.”). Furthermore, the skilled artisan would have had a reasonable expectation of success because growth hormone and long-acting GH both comprise growth hormone. There is no showing of art or record that the long-acting growth hormone of the claims of the ‘048 patent would be less effective than unmodified growth hormone of Takahashi.
Accordingly, instant claims 1-3 rendered obvious.
Regarding claims 4-6, claims 1-4, 6, 7 and 36 of the ‘048 patent teach that the chemical moiety covalently conjugated to growth hormone is a PEG-based moiety.
Regarding claim 8, the bond is a reversible covalent bond, e.g., self hydrolysable (autocleavage) (e.g., claims 1 and 7 of the ‘048 patent).
Regarding claim 14, Takahashi teaches that GH reduced steatosis (pp. 5-8, Fig 2).
Claims 1-6 and 14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 10098930 (hereinafter referred to as “the ‘930 patent”- cited in IDS filed 5/14/2024) in view of Takahashi (Int J Mol Sci 18:1447 (2017)- cited in IDS filed 4/15/2024).
The ‘930 patent is a CON of the ’048 patent.
The instant claims are drawn to a method of treating an inflammation-induced disease in a patient comprising administering a pharmaceutically effective amount of a long acting growth hormone to the patient.
The claims of the ‘930 patent are drawn to a prodrug conjugate of human growth hormone (hGH) of formula (I) or (II) wherein the hGH is covalent attached to a polymer, e.g., polyethylene glycol based (claims 1-7). Claim 10 of the ‘930 patent is drawn to a method for treatment of growth hormone related disease in a human person comprising administering a clinical effective amount of the pharmaceutical composition of claim 1 to the human person.
The claims of the ‘930 patent do not expressly teach a method of treating an inflammation-induced disease in a patient, e.g. NAFLD or NASH.
Takahashi teaches administering growth hormone for treating NASH or cirrhosis (e.g., abstract, p. 8). GH profoundly reduces visceral fat, which plays an important role in the development of NAFLD. Furthermore, GH directly reduces lipogenesis in the hepatocytes (e.g., abstract). Takahashi teaches owing to the increasing prevalence of obesity and type 2 diabetes (T2DM), non-alcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of chronic liver disease worldwide. NAFLD consists of non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), and encompasses liver conditions ranging from simple steatosis to cirrhosis (p. 1). GH replacement therapy drastically reversed NASH, concomitant with a decrease in inflammation and oxidative stress markers (p. 2).
It would have been obvious to one of ordinary skill in the art to administer a growth hormone (GH) to a patient with NAFLD or NASH in order to treat the liver disease, as taught by Takahashi. The skilled artisan would have been motivated to administer a long-acting growth hormone of the claims of the ‘930 patent in a method of treating NAFLD or NASH. The U.S. Federal Circuit has explicitly stated that in order to make a prima facie case of obviousness, the suggestion and motivation to combine the references need not be explicitly stated in the text of the references. In DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641 (Fed. Cir. 2006), the Court writes, “the suggestion test is not a rigid categorical rule. The motivation need not be found in the references sought to be combined, but may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself. In re Dembiczak, 175 F.3d 994, 999 [50 USPQ2d 1614] (Fed. Cir. 1999). As we explained in Motorola, Inc. v. Interdigital Tech. Corp., 121 F.3d 1461, 1472 [43 USPQ2d 1481] (Fed. Cir. 1997), ‘there is no requirement that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.’” See Dystar at 1645. “Our suggestion test is in actuality quite flexible and not only permits, but requires, consideration of common knowledge and common sense.” See Dystar at 1650. See also In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious.”). Furthermore, the skilled artisan would have had a reasonable expectation of success because growth hormone and long-acting GH both comprise growth hormone. There is no showing of art or record that the long-acting growth hormone of the claims of the ‘930 patent would be less effective than unmodified growth hormone of Takahashi.
Accordingly, instant claims 1-3 rendered obvious.
Regarding claims 4-6, claims 1-7 of the ‘930 patent teach that the chemical moiety covalently conjugated to growth hormone is a PEG-based moiety.
Regarding claim 14, Takahashi teaches that GH reduced steatosis (pp. 5-8, Fig 2).
Claims 1-6, 14, and 16-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10799563 (hereinafter referred to as “the ‘563 patent”- cited in IDS filed 5/14/2024) in view of Takahashi (Int J Mol Sci 18:1447 (2017)- cited in IDS filed 4/15/2024).
The instant claims are drawn to a method of treating an inflammation-induced disease in a patient comprising administering a pharmaceutically effective amount of a long acting growth hormone to the patient.
The claims of the ‘563 patent are drawn to a polymeric human growth hormone (hGH) prodrug/long-acting or a pharmaceutically acceptable salt thereof of formula (Ia) or (Ib). Claim 2 of the ‘563 patent teaches
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wherein D is an hGH moiety connected to the rest of the 60 implanted device allowing delivery of the invention or molecule through an amine functional group ; and pl , p2 , p3 , and p4 are independently an integer ranging from 180 to 240.
The claims of the ‘563 patent do not expressly teach a method of treating an inflammation-induced disease in a patient, e.g. NAFLD or NASH.
Takahashi teaches administering growth hormone for treating NASH or cirrhosis (e.g., abstract, p. 8). GH profoundly reduces visceral fat, which plays an important role in the development of NAFLD. Furthermore, GH directly reduces lipogenesis in the hepatocytes (e.g., abstract). Takahashi teaches owing to the increasing prevalence of obesity and type 2 diabetes (T2DM), non-alcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of chronic liver disease worldwide. NAFLD consists of non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), and encompasses liver conditions ranging from simple steatosis to cirrhosis (p. 1). GH replacement therapy drastically reversed NASH, concomitant with a decrease in inflammation and oxidative stress markers (p. 2).
It would have been obvious to one of ordinary skill in the art to administer a growth hormone (GH) to a patient with NAFLD or NASH in order to treat the liver disease, as taught by Takahashi. The skilled artisan would have been motivated to administer a long-acting growth hormone of the claims of the ‘563 patent in a method of treating NAFLD or NASH. The U.S. Federal Circuit has explicitly stated that in order to make a prima facie case of obviousness, the suggestion and motivation to combine the references need not be explicitly stated in the text of the references. In DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641 (Fed. Cir. 2006), the Court writes, “the suggestion test is not a rigid categorical rule. The motivation need not be found in the references sought to be combined, but may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself. In re Dembiczak, 175 F.3d 994, 999 [50 USPQ2d 1614] (Fed. Cir. 1999). As we explained in Motorola, Inc. v. Interdigital Tech. Corp., 121 F.3d 1461, 1472 [43 USPQ2d 1481] (Fed. Cir. 1997), ‘there is no requirement that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.’” See Dystar at 1645. “Our suggestion test is in actuality quite flexible and not only permits, but requires, consideration of common knowledge and common sense.” See Dystar at 1650. See also In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious.”). Furthermore, the skilled artisan would have had a reasonable expectation of success because growth hormone and long-acting GH both comprise growth hormone. There is no showing of art or record that the long-acting growth hormone of the claims of the ‘563 patent would be less effective than unmodified growth hormone of Takahashi.
Accordingly, instant claims 1-3 rendered obvious.
Regarding claims 4-6, claims 1 and 2 of the ‘563 patent teach that the chemical moiety covalently conjugated to growth hormone is a PEG-based moiety (-CH2-CH2-O-)n.
Regarding claim 14, Takahashi teaches that GH reduced steatosis (pp. 5-8, Fig 2).
Regarding claims 16-18, claim 2 of the ‘563 patent recites the structure of instant claim 16, wherein D is an hGH moiety connected to the rest of the molecule through an amine functional group; and p1, p2, p3, and p4 are independently an integer ranging from 180 to 240.
Regarding claim 19, claim 15 and 17 of the ‘563 patent recite a GH of SEQ ID NO:1, which has 100% identity with instant SEQ ID NO:1.
Regarding claim 20, claim 16 of the ‘563 patent recites wherein -D is connected to the rest of the molecule through an amine provided by a lysine side chain.
Claims 1-6, 14, and 16-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12133883 (hereinafter referred to as “the ‘883 patent”) in view of Takahashi (Int J Mol Sci 18:1447 (2017)- cited in IDS filed 4/15/2024).
The ‘883 patent is a CON of the ‘563 patent.
The instant claims are drawn to a method of treating an inflammation-induced disease in a patient comprising administering a pharmaceutically effective amount of a long acting growth hormone to the patient.
The claims of the ‘883 patent are drawn to a container comprising a polymeric human growth hormone (hGH) prodrug/long-acting or a pharmaceutically acceptable salt thereof of formula (Ia) or (Ib). Claim 2 of the ‘883 patent teaches
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wherein D is an hGH moiety connected to the rest of the molecule through an amine functional group; and p1, p2, p3, and p4 are independently an integer ranging from 180 to 240.
The claims of the ‘883 patent do not expressly teach a method of treating an inflammation-induced disease in a patient, e.g. NAFLD or NASH.
Takahashi teaches administering growth hormone for treating NASH or cirrhosis (e.g., abstract, p. 8). GH profoundly reduces visceral fat, which plays an important role in the development of NAFLD. Furthermore, GH directly reduces lipogenesis in the hepatocytes (e.g., abstract). Takahashi teaches owing to the increasing prevalence of obesity and type 2 diabetes (T2DM), non-alcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of chronic liver disease worldwide. NAFLD consists of non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), and encompasses liver conditions ranging from simple steatosis to cirrhosis (p. 1). GH replacement therapy drastically reversed NASH, concomitant with a decrease in inflammation and oxidative stress markers (p. 2).
It would have been obvious to one of ordinary skill in the art to administer a growth hormone (GH) to a patient with NAFLD or NASH in order to treat the liver disease, as taught by Takahashi. The skilled artisan would have been motivated to administer a long-acting growth hormone of the claims of the ‘883 patent in a method of treating NAFLD or NASH. The U.S. Federal Circuit has explicitly stated that in order to make a prima facie case of obviousness, the suggestion and motivation to combine the references need not be explicitly stated in the text of the references. In DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641 (Fed. Cir. 2006), the Court writes, “the suggestion test is not a rigid categorical rule. The motivation need not be found in the references sought to be combined, but may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself. In re Dembiczak, 175 F.3d 994, 999 [50 USPQ2d 1614] (Fed. Cir. 1999). As we explained in Motorola, Inc. v. Interdigital Tech. Corp., 121 F.3d 1461, 1472 [43 USPQ2d 1481] (Fed. Cir. 1997), ‘there is no requirement that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.’” See Dystar at 1645. “Our suggestion test is in actuality quite flexible and not only permits, but requires, consideration of common knowledge and common sense.” See Dystar at 1650. See also In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious.”). Furthermore, the skilled artisan would have had a reasonable expectation of success because growth hormone and long-acting GH both comprise growth hormone. There is no showing of art or record that the long-acting growth hormone of the claims of the ‘883 patent would be less effective than unmodified growth hormone of Takahashi.
Accordingly, instant claims 1-3 rendered obvious.
Regarding claims 4-6, claims 1 and 2 of the ‘883 patent teach that the chemical moiety covalently conjugated to growth hormone is a PEG-based moiety (-CH2-CH2-O-)n within the recited structures.
Regarding claim 14, Takahashi teaches that GH reduced steatosis (pp. 5-8, Fig 2).
Regarding claims 16-18, claim 2 of the ‘883 patent recites the structure of instant claim 16, wherein D is an hGH moiety connected to the rest of the molecule through an amine functional group; and p1, p2, p3, and p4 are independently an integer ranging from 180 to 240. Claims 17 and 18 of the ‘883 patent further recite wherein p1, p2, p3, and p4 are independently an integer ranging from 200 to 240.
Regarding claim 19, claims 14 and 16 of the ‘883 patent recite a GH of SEQ ID NO:1, which has 100% identity with instant SEQ ID NO:1.
Regarding claim 20, claim 15 of the ‘883 patent recites wherein -D is connected to the rest of the molecule through an amine provided by a lysine side chain.
Claims 1-6, 14, and 16-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 21-40 of copending Application No. 18/891744 (hereinafter referred to as “the ‘744 application”) in view of Takahashi (Int J Mol Sci 18:1447 (2017)- cited in IDS filed 4/15/2024).
The ‘744 application is a CON of the ‘883 patent.
This is a provisional nonstatutory double patenting rejection.
The instant claims are drawn to a method of treating an inflammation-induced disease in a patient comprising administering a pharmaceutically effective amount of a long acting growth hormone to the patient.
The claims of the ‘744 application are drawn to a liquid pharmaceutical formulation comprising 9 to 150 mg/mL of a polymeric human growth hormone (hGH) prodrug or a pharmaceutically acceptable salt thereof of formula (Ia) or (Ib). Claim 23 recites
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wherein D is an hGH moiety connected to the rest of the molecule through an amine functional group; and p1, p2, p3, and p4 are independently an integer ranging from 180 to 270, preferably from 200 to 250, even more preferably from 210 to 240 and most preferably from 220 to 240.
The claims of the ’74 application do not expressly teach a method of treating an inflammation-induced disease in a patient, e.g. NAFLD or NASH.
Takahashi teaches administering growth hormone for treating NASH or cirrhosis (e.g., abstract, p. 8). GH profoundly reduces visceral fat, which plays an important role in the development of NAFLD. Furthermore, GH directly reduces lipogenesis in the hepatocytes (e.g., abstract). Takahashi teaches owing to the increasing prevalence of obesity and type 2 diabetes (T2DM), non-alcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of chronic liver disease worldwide. NAFLD consists of non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), and encompasses liver conditions ranging from simple steatosis to cirrhosis (p. 1). GH replacement therapy drastically reversed NASH, concomitant with a decrease in inflammation and oxidative stress markers (p. 2).
It would have been obvious to one of ordinary skill in the art to administer a growth hormone (GH) to a patient with NAFLD or NASH in order to treat the liver disease, as taught by Takahashi. The skilled artisan would have been motivated to administer a long-acting growth hormone of the claims of the ‘744 application in a method of treating NAFLD or NASH. The U.S. Federal Circuit has explicitly stated that in order to make a prima facie case of obviousness, the suggestion and motivation to combine the references need not be explicitly stated in the text of the references. In DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641 (Fed. Cir. 2006), the Court writes, “the suggestion test is not a rigid categorical rule. The motivation need not be found in the references sought to be combined, but may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself. In re Dembiczak, 175 F.3d 994, 999 [50 USPQ2d 1614] (Fed. Cir. 1999). As we explained in Motorola, Inc. v. Interdigital Tech. Corp., 121 F.3d 1461, 1472 [43 USPQ2d 1481] (Fed. Cir. 1997), ‘there is no requirement that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.’” See Dystar at 1645. “Our suggestion test is in actuality quite flexible and not only permits, but requires, consideration of common knowledge and common sense.” See Dystar at 1650. See also In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious.”). Furthermore, the skilled artisan would have had a reasonable expectation of success because growth hormone and long-acting GH both comprise growth hormone. There is no showing of art or record that the long-acting growth hormone of the claims of the ‘744 application would be less effective than unmodified growth hormone of Takahashi.
Accordingly, instant claims 1-3 rendered obvious.
Regarding claims 4-6, claims 22 and 23 of the ‘744 application teach that the chemical moiety covalently conjugated to growth hormone is a PEG-based moiety (-CH2-CH2-O-)n within the recited structures.
Regarding claim 14, Takahashi teaches that GH reduced steatosis (pp. 5-8, Fig 2).
Regarding claims 16-18, claim 23 of the ‘744 application recites the structure of instant claim 16, wherein D is an hGH moiety connected to the rest of the molecule through an amine functional group; and p1, p2, p3, and p4 are independently an integer ranging from 180 to 270, preferably from 200 to 250, even more preferably from 210 to 240 and most preferably from 220 to 240.
Claims 1-6, 14, and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-36 of U.S. Patent No. 9511122 (hereinafter referred to as “the ‘122 patent”; cited in IDS filed 4/15/2024) in view of Takahashi (Int J Mol Sci 18:1447 (2017)- cited in IDS filed 4/15/2024).
The instant claims are drawn to a method of treating an inflammation-induced disease in a patient comprising administering a pharmaceutically effective amount of a long acting growth hormone to the patient.
The claims of the ‘122 patent are drawn to a dry composition comprising a therapeutically effective amount of a recombinant human growth hormone (“rhGH”) polymer prodrug and one or more lyoprotectants, wherein the rhGH is transiently linked via a reversible linker moiety to a polymer carrier; wherein the composition is stable for at least 6 months when stored at temperatures ranging from 2 to 25° C, and wherein during such storage less than 5% of the rhGH is released from the rhGH polymer prodrug as free rhGH. Claim 8 of the ‘122 patent recites
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wherein c is an integer between 250 to 750. Claim 24 of the ‘122 patent recites a reconstituted composition.
The claims of the ‘122 patent do not expressly teach a method of treating an inflammation-induced disease in a patient, e.g. NAFLD or NASH.
Takahashi teaches administering growth hormone for treating NASH or cirrhosis (e.g., abstract, p. 8). GH profoundly reduces visceral fat, which plays an important role in the development of NAFLD. Furthermore, GH directly reduces lipogenesis in the hepatocytes (e.g., abstract). Takahashi teaches owing to the increasing prevalence of obesity and type 2 diabetes (T2DM), non-alcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of chronic liver disease worldwide. NAFLD consists of non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), and encompasses liver conditions ranging from simple steatosis to cirrhosis (p. 1). GH replacement therapy drastically reversed NASH, concomitant with a decrease in inflammation and oxidative stress markers (p. 2).
It would have been obvious to one of ordinary skill in the art to administer a growth hormone (GH) to a patient with NAFLD or NASH in order to treat the liver disease, as taught by Takahashi. The skilled artisan would have been motivated to administer a long-acting growth hormone of the claims of the ‘122 patent in a method of treating NAFLD or NASH. The U.S. Federal Circuit has explicitly stated that in order to make a prima facie case of obviousness, the suggestion and motivation to combine the references need not be explicitly stated in the text of the references. In DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641 (Fed. Cir. 2006), the Court writes, “the suggestion test is not a rigid categorical rule. The motivation need not be found in the references sought to be combined, but may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself. In re Dembiczak, 175 F.3d 994, 999 [50 USPQ2d 1614] (Fed. Cir. 1999). As we explained in Motorola, Inc. v. Interdigital Tech. Corp., 121 F.3d 1461, 1472 [43 USPQ2d 1481] (Fed. Cir. 1997), ‘there is no requirement that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.’” See Dystar at 1645. “Our suggestion test is in actuality quite flexible and not only permits, but requires, consideration of common knowledge and common sense.” See Dystar at 1650. See also In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious.”). Furthermore, the skilled artisan would have had a reasonable expectation of success because growth hormone and long-acting GH both comprise growth hormone. There is no showing of art or record that the long-acting growth hormone of the claims of the ‘122 patent would be less effective than unmodified growth hormone of Takahashi.
Accordingly, instant claims 1-3 rendered obvious.
Regarding claims 4-6, claims 7 and 8 of the ‘122 patent teach that the chemical moiety covalently conjugated to growth hormone is a PEG-based moiety (-CH2-CH2-O-)n within the recited structures.
Regarding claim 14, Takahashi teaches that GH reduced steatosis (pp. 5-8, Fig 2).
Regarding claim 19, claim 16 of the ‘122 patent recites a GH of SEQ ID NO:1, which has 100% identity with instant SEQ ID NO:1.
Claims 1-6, 8, 14, and 15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9919033 (hereinafter referred to as “the ‘033 patent”; cited in IDS filed 4/15/2024) in view of Takahashi (Int J Mol Sci 18:1447 (2017)- cited in IDS filed 4/15/2024).
The ‘033 patent is a CON of the ‘122 patent.
The instant claims are drawn to a method of treating an inflammation-induced disease in a patient comprising administering a pharmaceutically effective amount of a long acting growth hormone to the patient.
The claims of the ‘033 patent are drawn to a pen injector comprising a cartridge comprising a dry composition comprising a therapeutically effective amount of a recombinant human growth hormone (“rhGH”) polymer prodrug; and a lyoprotectant; wherein the rhGH is transiently linked via a reversible linker moiety to a polymer carrier, and wherein the composition is stable for at least 6 months when stored at temperatures ranging from 2 to 25° C., where during such storage less than 5% of the rhGH is released from the rhGH polymer prodrug as free rhGH. Claim 10 of the ‘033 patent recites
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wherein c is an integer between 250 to 750. Claims 18-20 24 of the ‘033 patent recite that the pen injector comprises a reconstituted solution.
The claims of the ‘033 patent do not expressly teach a method of treating an inflammation-induced disease in a patient, e.g. NAFLD or NASH.
Takahashi teaches administering growth hormone for treating NASH or cirrhosis (e.g., abstract, p. 8). GH profoundly reduces visceral fat, which plays an important role in the development of NAFLD. Furthermore, GH directly reduces lipogenesis in the hepatocytes (e.g., abstract). Takahashi teaches owing to the increasing prevalence of obesity and type 2 diabetes (T2DM), non-alcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of chronic liver disease worldwide. NAFLD consists of non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), and encompasses liver conditions ranging from simple steatosis to cirrhosis (p. 1). GH replacement therapy drastically reversed NASH, concomitant with a decrease in inflammation and oxidative stress markers (p. 2).
It would have been obvious to one of ordinary skill in the art to administer a growth hormone (GH) to a patient with NAFLD or NASH in order to treat the liver disease, as taught by Takahashi. The skilled artisan would have been motivated to administer a long-acting growth hormone of the claims of the ‘033 patent in a method of treating NAFLD or NASH. The U.S. Federal Circuit has explicitly stated that in order to make a prima facie case of obviousness, the suggestion and motivation to combine the references need not be explicitly stated in the text of the references. In DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641 (Fed. Cir. 2006), the Court writes, “the suggestion test is not a rigid categorical rule. The motivation need not be found in the references sought to be combined, but may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself. In re Dembiczak, 175 F.3d 994, 999 [50 USPQ2d 1614] (Fed. Cir. 1999). As we explained in Motorola, Inc. v. Interdigital Tech. Corp., 121 F.3d 1461, 1472 [43 USPQ2d 1481] (Fed. Cir. 1997), ‘there is no requirement that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.’” See Dystar at 1645. “Our suggestion test is in actuality quite flexible and not only permits, but requires, consideration of common knowledge and common sense.” See Dystar at 1650. See also In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious.”). Furthermore, the skilled artisan would have had a reasonable expectation of success because growth hormone and long-acting GH both comprise growth hormone. There is no showing of art or record that the long-acting growth hormone of the claims of the ‘033 patent would be less effective than unmodified growth hormone of Takahashi.
Accordingly, instant claims 1-3 rendered obvious.
Regarding claims 4-6, claims 9 and 10 of the ‘033 patent teach that the chemical moiety covalently conjugated to growth hormone is a PEG-based moiety.
Regarding claim 8, claims 1 and 9 of the ‘033 patent teaches that the rhGH is transiently linked via a reversible linker moiety to a polymer carrier.
Regarding claim 14, Takahashi teaches that GH reduced steatosis (pp. 5-8, Fig 2).
Regarding claim 15, claim 13 of the ‘033 patent recites that one application of the rhGH polymer prodrug is sufficient for one week.
Conclusion
No claims are allowed.
Claims 1-26 are pending. Claims 7, 9-10, and 21 are withdrawn.
Claims 1-6, 8, 11-20, and 22-26 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTINA M HELLMAN whose telephone number is (571)272-2836. The examiner can normally be reached M-F 9:00 am-5:30 pm.
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/KRISTINA M HELLMAN/Examiner, Art Unit 1654
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