DETAILED 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 .
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.
Priority
The instant application, filed 02/25/2024, is a 371 filing of PCT/CN2022/106115, filed 07/15/2022, and claims foreign priority to CN202110982310.8, filed 08/25/2021.
Status of Claims/Application
Applicant’s preliminary amendment of 02/25/2024 is acknowledged. Claims 3, 5-8, 10, and 12-14 are amended and claims 15-19 are new. Claims 1-19 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 02/26/2024, 07/11/2025, and 10/17/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Objections
Claims 12 and 17 are objected to for the following informalities: Claim 12, line 3, and claim 17, line 2, recite “3 x 10 4IU” with a space between “10” and “4”. Correction to “3 x 104 IU” is suggested to clearly indicate 104.
Claim Rejections - 35 USC § 112(b)
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 2, 4, 7, 9, 11-13, and 16-18 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.
Claims 2, 4, 7, 9, 11-13, 16, and 18 recite the term “preferably” as follows:
Claim 2, lines 4-7: “preferably, the amino acid at position 125 of the amino acid sequence as shown in SEQ ID NO: 1 is not cysteine”;
Claim 2, lines 6-7: “preferably, the amino acid at position 125 of the amino acid sequence as shown in SEQ ID NO: 1 is replaced with serine or alanine”;
Claim 4, lines 3-4: “preferably the linking peptide has a general formula of (GnS)m, in which n is an integer selected from…”;
Claim 7, lines 3-4: “preferably, the expression system is CHO-K1 cell, which is deposited…”;
Claim 9, lines 3-4: “preferably, the dosage form is selected from solution for injection or lyophilized powder for injection”;
Claim 9, lines 5-6: “preferably, the carrier is selected from excipient, diluent…”;
Claim 11, lines 2-3: “preferably, is injected subcutaneously or intravenously”;
Claim 12, lines 3-4, “preferably, the pharmaceutical composition is administered at…”;
Claim 13, lines 2-4, “preferably every 14-28 days; preferably, the pharmaceutical composition is administered every 7-28 days, preferably every 14-28 days”;
Claim 16, line 2, “preferably is injected subcutaneously or intravenously”;
Claim 18, line 2, “preferably every 14-28 days”
The use of “preferably” in these instances render the claims indefinite as it is unclear if the limitations that follow the term, which are narrower embodiments of the preceding limitations, are part of the claimed invention or exemplary embodiments. MPEP 2173.05(d) states “Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim.”
Additionally, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims recite a broad recitation, and the claim also recites preferable limitations which are the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 2 recites that the fusion protein includes the amino acid sequences shown in SEQ ID NOs: 1 and 2. The claim further recites that preferably the amino acid in position 125 of SEQ ID NO: 1 is not cysteine; preferably the amino acid in position 125 of SEQ ID NO: 1 is replaced with serine or alanine. SEQ ID NO: 1 is a specific amino acid sequence that has an alanine in position 125. As the claim recites that the fusion protein includes SEQ ID NO: 1, which has an alanine in position 125, it is unclear how the preferable limitations are intended to limit the claim. Particularly as the amino acid in position 125 of SEQ ID NO: 1 is already not cystine and is already alanine. It is also unclear how the fusion protein can include SEQ ID NO: 1 and have a serine in position 125 as this position in SEQ ID NO: 1 is alanine.
Claim 4 recites that the linking peptide has a general formula of (GnS)m in which “n or m is an integer selected from 1 to 10”. It is unclear if the limitation is intended to limit both n and m to individually being an integer from 1 to 10 or if, for instance, n could be an integer from 1 to 10 and m could be any integer including those outside of the recited range. As the scope of the claim is unclear, the claim is indefinite. Additionally, the claim recites that, preferably, n is an integer selected from 1 to 4, and m is an integer selected from “0 to 3”. If applicant’s intention is to claim that both n and m are individually 1 to 10, then it is unclear how m could be 0. Additionally, it is noted that, in the case that m is 0 in the general formula of (GnS)m, in the broadest reasonable interpretation of the claim the linker would not exist.
Appropriate correction/clarification is required.
Claims 11-13 recite “the pharmaceutical composition”. There is insufficient antecedent basis for this limitation in the claims. Claims 11 and 12 depend on claim 10 and claim 13 depends on claim 11 and ultimately on claim 10. Claim 10 is drawn to a method for treating or preventing LAS comprising administrating the fusion protein defined in claim 1. Neither claim 1 nor 10 recite a pharmaceutical composition that could be being referenced rendering the metes and bounds of the claims indefinite.
Claims 12 and 17 recite the limitations that the fusion protein (claim 12) or the pharmaceutical composition (claim 17) is administered at 3x104 IU to 1x106 IU “each dose” (claim 12 lines 2 and 3-4; claim 17, line 2). There is insufficient antecedent basis for “each dose” in the claims. Specifically, it is unclear what “each dose” is referencing as neither claim 10 nor 15, upon which the claims depend, require multiple dosages. As such, the metes and bounds of the claims are indefinite.
Provisional Statutory Double Patenting (35 U.S.C. 101)
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claims 1-9 are provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1-9 of copending Application No. 18/686,480. This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented.
Instant claims 1-9 recite limitations that are identical to those recited in claims 1-9 of App’480, respectively. As such the scope of the inventions are the same and the inventions are drawn to identical subject matter.
Claim Rejections - 35 USC § 112(a) Enablement
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.
Claim 7 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The instant claim recites a deposited biological material, specifically the CHO-K1 cell, which is deposited in China General Microbiological Culture Collection Center on May 26, 2022, under CGMCC No. 45173. Since the deposited biological material is essential to the claimed invention, it must be readily available to the public. However, it is not apparent that the biological materials are readily available to the public as there is no indication in the specification as to public availability as required by 37 C.F.R. 1.808.
US patent applications comprising a biological deposit in addition to adherence to the Budapest Treaty, must further comply with 37 C.F.R. 1.808 (a) in which a person in position to assert that the deposit was made under conditions that assure that:
(1) Access to the deposit will be available during pendency of the patent application making reference to the deposit to one determined by the Director to be entitled thereto under § 1.14 and 35 U.S.C. 122, and
(2) Subject to paragraph (b) of this section, all restrictions imposed by the depositor on the availability to the public of the deposited material will be irrevocably removed upon the granting of the patent.
An affidavit or declaration by Applicant, or a statement by an attorney of record over his or her signature and registration number, stating that the specific biological materials that have been deposited under the Budapest Treaty and that the biological materials will be irrevocably and without restriction or condition released to the public upon the issuance of a patent, would satisfy the deposit requirement made herein.
Applicant may provide assurance of compliance by an affidavit or declaration, or by a statement by an attorney of record over his or her signature and registration number, showing that:
(a) during the pendency of this application, access to the invention will be afforded to the Commissioner upon request;
(b) all restrictions upon availability to the public will be irrevocably removed upon granting of the patent;
(c) the deposit will be maintained in a public depository for a period of 30 years or 5 years after the last request or for the effective life of the patent, whichever is longer;
(d) a test of the viability of the biological material at the time of the deposit will be made (see 37 C.F.R. 1.807); and
(e) the deposit will be replaced if it should ever become inviable.
Because the condition of 37 CFR 1.808(a) has not been met the claim 7 is rejected under 35 USC 112(a) as failing to provide an enabling disclosure.
Claims 10-19 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 treatment of ALS, does not reasonably provide enablement for prevention of ALS. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue,’ not 'experimentation.'" (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The nature of the invention
The instantly claimed invention is drawn to methods of treating or preventing ALS comprising administering to a subject an effective amount of a hIL-2 – HSA fusion protein having the structure recited in instant claim 1 or a pharmaceutical composition comprising the fusion protein and a pharmaceutically acceptable carrier as recited in instant claim 8.
Instant claims 14 and 19 also claim that the fusion protein or pharmaceutical composition is capable of preventing or treating decrease in limb strength, body weight, and/or neurological function caused by ALS.
The breadth of the claims
The claims are broad in that they encompass prevention of ALS and symptoms thereof.
With regards to “prevention”, the instant specification, page 8, lines 34-37, states “The term ‘prevention’ as used herein means the likelihood of at least reducing the risk (or susceptibility) to developing a disease or condition (i.e., [stopping] at least one clinical symptom of the disease that has not developed in a patient who may be exposed or susceptible to the disease but has not experienced or showed the symptoms of the disease).”
Based on this definition, the claim to “preventing” ALS encompasses embodiments in which the claimed method stops at least one clinical symptom of the disease that has not developed in a patient who may be exposed or susceptible to the disease but has not experienced or showed the symptoms of the disease. As such, the claims encompass an embodiment in which onset of ALS never occurs and the patient does not develop any clinical symptoms.
The amount or direction provided by the inventor / the existence of working examples
Example 7 of the instant specification evaluated the preventative and therapeutic effects of the IL-2-HSA fusion protein on spontaneous ALS disease in mouse models (page 13). The study included 19 mice with 4 controls and 15 mice randomly divided into three groups by body weight. Group G1 was a wild-type control; group G2 a model control; group G3 received Edaravone treatment; and group G4 received treatment with the IL-2-HSA fusion protein. The example details the use of ALS transgeneic B6SJL-Tg (SOD 1-G93A) transgeneic mice (page 13, lines 6-19). The example concludes that IL-2-HSA fusion protein significantly improved survival rates and survival cycles of transgenic mice (SOD1-G93A) with spontaneous ALS. With the changes of the body weights, neurological scores, and survival cycles of the mice, it shows that the IL-2-HSA fusion protein was superior to Edaravone in efficacy, and may produce less adverse reactions to the body.
While the example demonstrates that survival rate and survival cycles can be significantly increased in ALS transgeneic mice using the claimed fusion protein, the example does not necessarily demonstrate prevention of ALS or symptoms thereof using the claimed method. Additionally, neither the example nor the disclosure provide a method that would allow an ordinarily skilled artisan to identify patients that would predictably develop ALS such that it could be established that the disease, or at least one symptom thereof, was prevented using the claimed methods.
The state of the prior art / the level of predictability in the art
The prior art also does not provide a method that could be used by one of ordinary skill in the art to predictably identify patients that would have developed ALS without the claimed method in order to establish that the claimed method resulted in prevention of the disease. Rather, the art suggests that the development and onset of ALS is unpredictable.
For instance MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US); accessed on 07/10/2026 from https://medlineplus.gov/genetics/condition/amyotrophic-lateral-sclerosis/ (9 pages) teaches that there are many different types of ALS distinguished by their signs and symptoms and their genetic cause or lack of a clear genetic association. Most people with ALS have a form of the condition that is described as sporadic, which means it occurs in people with no apparent history of the disorder in their family. A small proportion of people with ALS, estimated at 5-10% have a family history of ALS or a related condition called frontotemporal dementia (FTD) (page 1, paragraph 2). MedlinePlus teaches that the first signs and symptoms of ALS may be so subtle that they are overlooked and that most people with ALS die from respiratory failure within 2 to 10 years after signs and symptoms first appear (page 1, paragraph 3).
MedlinePlus teaches that mutations in several genes can cause familial ALS and contribute to the development of sporadic ALS. Mutations of the C9orf72 gene account for 30-40% of familial ALS in the US and Europe. Worldwide, SOD1 gene mutations cause 15-20% of familial ALS and TARDBP mutations account for 5% of cases. The other genes that have been associated with familial ALS each account for a small portion of cases. It is estimated that 60 percent of individuals with familial ALS have an identified genetic mutation. The cause of the condition in the remaining individuals is unknown (page 2, Causes, paragraph 1). The causes of sporadic ALS is largely unknown but probably involves a combination of genetic and environmental factors. While genetic variations have been associated with sporadic ALS, not all genetic factors have been identified and it is unclear how most genetic changes influence the development of the disease. People with a gene variation that increases their risk of ALS likely require additional genetic and environmental triggers to develop the disorder (page 3, paragraph 2). About 90-95 percent of ALS cases are sporadic, which means they are not inherited (page 4, paragraph 1).
Ingre, C., et al (2015) Risk factors of amyotrophic lateral sclerosis Clinical Epidemiology 7; 181-193 teaches that, although recent genetic studies had substantially improved understanding of the causes of ALS, especially familial ALS, an important role of non-genetic factors in ALS is recognized and needs to be further studied. Ingre provides a review discussing several major genetic contributors to ALS identified to date, followed by a more focused discussion on the most commonly examined non-genetic risk factors for ALS. Ingre reviews factors related to lifestyle choices, including smoking, intake of antioxidants, physical fitness, body mass index, and physical exercise, followed by factors related to occupational and environmental exposures, including electromagnetic fields, metals, pesticides, B-methylamino-L-alanine, and viral infections. Potential links between ALS and other medical conditions, including head trauma, metabolic diseases, cancer, and inflammatory diseases are also discussed (abstract). Ingre also teaches that although many non-genetic risk factors have been described for ALS, their interaction with different genetic backgrounds relevant to ALS remains elusive. This is likely due to the fact that ALS is a rare disease and single-center studies usually lack sufficient statistical power to test for gene-environment interactions (page 187, left column, last paragraph).
The teachings of MedlinePlus and Ingre demonstrate that the onset of ALS is not predictable and can be sporadic and/or stem from a multitude of risk factors including genetic, environmental, occupational and lifestyle choices and the interaction of these factors.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
In order to practice the invention as claimed, one of ordinary skill in the art would be required to undergo undue experimentation in an effort to identify a method that could be used to predictably identify subjects who would develop ALS in order to establish that the claimed method resulted in the prevention of the disease. As discussed above, the art indicates that the development of ALS is unpredictable and can be the result of a variety of factors, which further suggests a high likelihood that no such method could be found.
In view of the Wands factors discussed above, a person of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the claimed invention. As such, the instant claims were determined to not meet the scope of enablement requirement of 35 USC 112(a).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 3-4 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US 2019/0062395 A1 (Merchant, F. and S. Fidai) 28 Feb 2019.
US’395 teaches human interleukin-2 (IL-2) muteins or variants thereof (abstract). US’395 further teaches that the IL-2 muteins can be prepared as a fusion or chimeric polypeptide that include a subject IL-2 mutein and a heterologous polypeptide. Exemplary heterologous polypeptides can increase circulating half-life of the chimeric polypeptide in vivo, and may, therefore, further enhance the properties of the mutein IL-2 polypeptides. US’395 also teaches that the polypeptide that increases circulating half-life may be a serum albumin, such as human serum albumin (page 11, [0129]).
US’395 further teaches that the IL-2 mutein can be linked directly or indirectly to the heterologous fusion protein (page 11, [0131]).
US’395 provides exemplary IL-2 extended half-life fusion amino acid sequences in table 5 (pages 17-22 [0152]). Of these, SEQ ID NOs: 62-75 all comprise an albumin amino acid sequence that is identical to instant SEQ ID NO: 2. As an example, instant SEQ ID NO: 2 is shown aligned with US’395, SEQ ID NO: 62 below:
PNG
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779
630
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The fusion sequences disclosed by US’395, SEQ ID NOs: 62-75 also comprise human IL-2 sequences that are at least 90% identical to instant SEQ ID NO: 1. For instance, instant SEQ ID NO: 1 aligned with US’395, SEQ ID NO: 62 is shown below, and has 96.6% sequence identity:
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298
616
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The alignment of US’395, SEQ ID NOs: 63-75 with instant SEQ ID NO: 1 also have sequence identity higher than 90% as follows:
SEQ ID NO:
% identity
SEQ ID NO:
% identity
SEQ ID NO:
% identity
63
94.1%
68
95.9%
73
95.9%
64
94.5%
69
95.7%
74
95.9%
65
95.9%
70
94.5%
75
95.7%
66
93.8%
71
95.9%
67
95.9%
72
93.8%
Additionally, all of US’395, SEQ ID NOs: 62-75 comprise a human IL-2 variant fused to albumin via a (G4S)3 linker, which meets the instant claim 3 limitation of a linking peptide and the instant claim 4 limitation of the linking peptide having a general formula of (GnS)m, when n is 4 and m is 3.
Thus, US’395 anticipates instant claims 1 and 3-4.
Claims 1-4, 6, and 8 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by US 2007/0048282 A1 (Rosen, C.A., et al) 01 MAR 2007.
US’282 teaches albumin fusion proteins, nucleic acid molecules encoding the albumin fusion proteins, vectors containing the nucleic acids and host cells transformed with the nucleic acid vectors as well as methods of making the albumin fusion proteins. Additionally, US’282 discloses pharmaceutical compositions comprising the albumin fusion proteins (abstract).
US’282 teaches that the albumin fusion protein comprises a therapeutic protein or portion corresponding to a therapeutic protein disclosed in column 1 of table 1 (“therapeutic protein: X”), which includes Interleukin 2 (IL-2) (page 2, [0012]; Table 1, page 14, row 2). US’828 further provides amino acid and nucleic acid sequences for IL2:HSA fusion proteins in table 2 on page 19 (page 19, Table 2, fusion numbers 28-32). Fusion no. 27, construct 1757, is a mature human IL-2 with a single amino acid mutation of C to S at position 145 cloned downstream of HSA with a HSA/kex2 leader sequence and is presented as amino acid SEQ ID NO: 175 and nucleic acid SEQ ID NO: 143.
US’282, SEQ ID NO: 175 comprises a human interleukin 2 sequence that is fused directly to human HSA. SEQ ID NO: 175 comprises a sequence that is 99.6% identical to instant SEQ ID NO: 1 as shown in the ABSS alignment below:
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302
617
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As shown in the alignment above, the IL-2 sequence in the fusion protein of US’282, SEQ ID NO: 175, differs in a single conservative substitution in position 125 of instant SEQ ID NO: 1. Specifically the sequence disclosed by US’282 has a serine in place of the alanine, which meets the limitations of instant claim 2 if the claim is interpreted as encompassing variants of SEQ ID NO: 1 with the preferred limitations. It is noted that, while US’282 references the cystine to serine substitution as being in position 145 of the sequence, the position of the substitution is the same as the instantly claimed 125 position in SEQ ID NO: 1, as is shown in the alignment above.
US’282, SEQ ID NO: 175 also comprises a human HSA sequence that is identical to instant SEQ ID NO: 2, as shown in the alignment below:
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783
644
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In the construct disclosed by US’282, the IL-2 and HSA proteins are fused directly which meets the instant claim 4 limitation in which m can be 0, which would indicate that the (GnS)m linker is not required.
US’282 further teaches constructs comprising the above human IL-2 and HSA sequences with different leader sequences and with the IL-2 downstream of HSA (page 19, Fusion Nos. 28-32) demonstrating alternative orders and the use of alternative leader sequences.
US’282 further teaches nucleic acids encoding the fusion proteins (Table 2, page 19, “SEQ ID NO: X” column) and teaches its inclusion in expression vectors (Table 2, “Expression Vector” column).
US’282 further teaches pharmaceutical compositions comprising a therapeutically effective amount of the fusion proteins and a pharmaceutically acceptable carrier (pages 46-47, [0267]).
Thus, US’282 anticipates instant claims 1-4, 6, and 8.
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.
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.
Claims 1-4 and 6-9 are rejected under 35 U.S.C. 103 as being unpatentable over US 2007/0048282 A1 (Rosen, C.A., et al) 01 MAR 2007.
US’282 teaches the fusion protein of claim 1 as discussed in detail above.
US’282, however, does not exemplify CHO cells containing the nucleic acid molecule as recited in claim 7 or a specific dosage form of the pharmaceutical composition as recited in claim 9.
As discussed above, US’282 teaches nucleic acids encoding the fusion proteins and teaches the inclusion of the nucleic acid in an expression vector for introduction into a host cell (abstract). US’282 further teaches that the host cell can be a CHO cell (page 24, [0075]).
US’282 further teaches that the albumin fusion proteins disclosed, or formulations thereof, may be administered by any conventional method including parenteral, e.g., subcutaneous or intramuscular, injection or intravenous infusion. The treatment may consisting of a single dose or plurality of dosages over a period of time (page 70, [0568]-[0569]).
US’282 further teaches that the fusion proteins are well suited for formulation in aqueous carriers because of their extended shelf-life in solution (page 70, [0570]).
Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and solutes which render the formulation appropriate for the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules, vials or syringes, and may be stored in a freeze-dried (lyophilized) condition requiring on the addition of the sterile liquid carrier, for example water for injections, immediately prior to use (page 71, [0575]).
US’282 also teaches that the carrier suitably contains minor amounts of additives including non-ionic surfactants such as polysorbates, poloxamers, or PEG (page 72, [0591]). US’282 also teaches that the formulations can include excipients and stabilizers (page 72, [0592]), semisolid or liquid filler and diluent (page 72, [0583]), binders, wetting or emulsifying agents (page 47, [0267]).
US’282 further teaches that the pharmaceutical formulation can be in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, and the like (page 47, [0267]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to use a CHO cell as the host cell and to formulate the fusion protein disclosed by US’282 in accordance with the teachings of US’282 as a whole. It would have been obvious to use a CHO cell and to formulate the fusion protein according to the teachings of US’282 as a whole, and one of ordinary skill in the art would have had a reasonable expectation of success, as US’282 teaches the expression of the disclosed fusion proteins from cells including CHO cells and also teaches formulations that are suitable for the fusion proteins.
Claims 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over US 2007/0048282 A1 (Rosen, C.A., et al) 01 MAR 2007 as applied to claim 1 above, and in further view of US 2014/0315817 A1 (Schmidt, M.M., et al) 23 Oct 2014.
Claims 3-4 were rejected over US’282 as discussed in detail above. The claims are further rejected here to demonstrate that the linker claimed in instant claim 4 would have also been obvious in embodiments in which m is not equal to 0.
US’282 teaches the fusion protein of claim 1 as discussed in detail above.
US’282 further teaches that the therapeutic protein can be fused to the N- or C- terminus of an albumin or variant thereof and can also be joined through peptide linkers (page 50, [0301]).
US’282; however, does not teach that the linker comprises the general formula as recited in claim 4.
US’817 teaches variant serum albumin amino acid sequences and teaches fusion proteins in which the albumin amino acid sequence is fused to a therapeutic or a diagnostic agent, such as a therapeutic protein or a functional fragment or variant thereof that maintains activity and exhibits improved properties (abstract).
US’817 teaches that an exemplary sequence of a human serum albumin (HSA) in its mature form, is a 585 amino acid polypeptide as is shown in SEQ ID NO: 2 (page 6, [0065]-[0067]), which is identical to instant SEQ ID NO: 2 and the HSA sequence used in the fusion proteins disclosed by US’282.
US’817 also teaches that the therapeutic protein attached to the serum albumin is IL-2, e.g., human IL-2 or a biologically active variant or fragment thereof. Human IL-2 is a 153 amino acid protein, including a 20 amino acid N-terminal signal peptide. An exemplary IL-2 peptide sequence is the sequence of human IL-2, which is provided as SEQ ID NO: 11. US’817 teaches that the low dose IL-2 can be used to specifically induce Treg proliferation and promote an anti-inflammatory state. In particular, low-dose IL-2 can be administered subcutaneously, for example using a self-administered pen or cartridge device, such as those used with other self-administered peptide biotherapeutic drugs, such as long acting insulin. Advantages of using a variant albumin serum in association with IL-2 includes extending the PK of the IL-2. The extended PK can have advantages; for example, the IL-2 can be administered less frequently and/or at reduced concentrations and/or more consistent delivery levels of IL-2 can be achieved (page 11, [0124] – page 12, [0127])
US’817 teaches that, in some embodiments, the serum albumin is physically attached to the agent, including directly attached or attached via a linker (page 18, [0190]).
The linker includes one or more peptide bonds, e.g., generated by recombinant techniques or peptide synthesis. The linker can contain one or more amino acid residues that provide flexibility. In some embodiments, the linker peptide predominantly includes amino acid residues such as Gly, Ser, Ala, and/or Thr. The linker peptide should have a length that is adequate to link the two molecules in a way that they assume the correct conformation relative to one another so that they retain the desired activity. Suitable lengths include at least one, but not more than 30, amino acid residues. Exemplary linkers include glycine-serine polymers, including, for example, (GS)n, (GSGGS)n, (GGGGS)n, and (GGGS)n, where n is an integer of at least one, e.g., one, two, three, or four (page 18, [0190]-[0194]).
US’817 also exemplifies a fusion protein of HSA and IL-2. Although US’817 does not explicitly provide the entire sequence of the fusion protein that was produced, US’817 does teach that the linker used was a (G4S)3 linker (pages 24-25, examples 8-9).
US’817 also teaches isolated, recombinant DNA molecules and/or nucleotide sequences that encodes the disclosed proteins and teaches host cells, including recombinant CHO cells, transformed with the nucleotide sequence encoding the protein (page 2, [0024]-[0025]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the fusion protein disclosed by US’282 by substituting a peptide linker to join the IL-2 and HSA, including, for example, (GS)n, (GGGGS)n, and (GGGS)n, where n is an integer of at least one, e.g., one, two, three, or four, as disclosed by US’817 as an alternative to direct fusion. It would have been obvious to use a peptide linker in place of direct fusion, and one of ordinary skill in the art would have had a reasonable expectation of success, as US’282 teaches that a linker can be used to join the HSA and therapeutic protein and US’817 also teaches that HSA can be fused with a therapeutic protein, including IL-2, through direct fusion or with one of the disclosed linkers. Additionally, US’817 exemplifies an IL-2-HSA fusion protein that uses was a (G4S)3 linker, demonstrating the use of the linker in the same type of fusion protein as that disclosed by US’282.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over US 2007/0048282 A1 (Rosen, C.A., et al) 01 MAR 2007 as applied to claim 1 above, and in further view of Rodriguez-Silva, A., et al (2001) Scale-up purification of a mutant of recombinant human interleukin 2 by reverse-phase high performance liquid chromatography Biotecnolgia Aplicada 18; 159-162 and US 2014/0315817 A1 (Schmidt, M.M., et al) 23 Oct 2014.
US’282 teaches the fusion protein of claim 1 as discussed in detail above.
As discussed in detail above, US’282 teaches fusion no. 27, construct 1757, which is a mature human IL-2 with a single amino acid mutation of C to S at position 145 cloned downstream of HSA with a HSA/kex2 leader sequence and is presented as amino acid SEQ ID NO: 175.
This construct has the following alignment with instantly claimed SEQ ID NO: 4:
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As shown in the alignment above, the fusion protein disclosed by US’282 differs from the instantly claimed fusion protein in the serine that is in position 125 of the hIL-2 (position 145 if the signal peptide of native hIL-2 is included) of the fusion protein of US’282 versus the alanine of the instantly claimed fusion protein. Additionally, the hIL-2 of US’282 is directly fused to the HSA wherein the instantly claimed fusion protein uses a (G4S)2 linker.
US’282 does not teach the fusion protein of instant SEQ ID NO: 4.
Rodriguez-Silva teaches that IL-2 was initially described as a T cell growth factor and since then several functions have been ascribed to this lymphokine which plays a central role in immunity (page 159, left col., paragraph 1). Different procedures have been utilized for the purification of human recombinant IL-2 (rhIL-2) from insoluble protein aggregates. The purification of a mutant rhIL-2 where the Cys-125 was substituted for serine has also been reported (page 159, right col., paragraph 1). Rodriguez-Silva presents a procedure for scaling up the RP-HPLC purification step for a recombinant analogue of hIL-2 produced by replacing Cys-125 with alanine (rhIL-2A125) (page 159, right col., paragraph 2).
Rodriguez-Silva teaches that human rhIL-2A125 was produced by replacing the cystine at position 125 with alanine using site-directed mutagenesis so that the intramolecular disulfide bond could only be formed between Cys-58 and Cys-105, as necessary for obtaining fully active molecules. This procedure avoided contamination of incorrectly folded species, which in intact IL-2 preparations mainly results from isomerization of disulfide bonds due to the presence of the free, reactive sulfydryl group in Cys-125. In addition, through this substitution IL-2 oxidative dimerization is largely abrogated. These non-desired species that are commonly found in recombinant IL-2 preparations, reduce the refolding yield and sometimes the specific activity of the final products (page 161, left col., paragraph 1).
Rodriguez-Silva concludes that the data presented demonstrates the suitability of high-scale RP-HPLC as the main purification step for obtaining homogeneous preparations of the recombinant IL-2 analogue rhIL-2A125. The IL-2 preparations obtained from the disclosed procedure have adequate chemical and biological properties. In the case of rhIL-2A125, Rodriguez-Silva reports a practical approach to obtaining large amounts of the biologically active analogue of IL-2 (page 162, right col., paragraph 4).
The teachings of US’817 are as discussed in detail above.
As discussed above, US’817 teaches fusion proteins of hIL-2 and HSA and teaches that the proteins can be directly fused or fused via a linker including (GGGGS)n, where n is an integer including two (page 18, [0190]-[0194]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the fusion protein disclosed by US’282 by substituting the serine in position 125 of the hIL-2 in the fusion protein with alanine as disclosed by Rodriguez-Silva and by further using a peptide linker to join the IL-2 and HSA, including, (GGGGS)n where n is two as disclosed by US’817 as an alternative to direct fusion.
It would have been obvious to substitute the serine in the hIL-2 of the fusion protein with alanine as Rodriguez-Silva teaches that this cystine has been substituted for serine in other reports and also demonstrates substitution of the cystine with alanine. Additionally, US’817 motivates the substitution of the cystine with alanine teaching that by replacing the cysteine at position 125 with alanine, the intramolecular disulfide bond can only form between Cys-58 and Cys-105, which is necessary for obtaining fully active molecules. Additionally, the disclosed procedure avoids contamination of incorrectly folded species and abrogates IL-2 oxidative dimerization. An ordinary skilled artisan would have had a reasonable expectation of success as Rodriguez-Silva teaches alanine as an alternative to serine substitution and both US’282 and Rodriguez-Silva teach substitution of the same cystine in hIL-2.
It would have been obvious to use the peptide linker (GGGGS)n, where n is 2, in place of direct fusion, and one of ordinary skill in the art would have had a reasonable expectation of success, as US’282 teaches that a linker can be used to join the HSA and therapeutic protein and US’817 also teaches that HSA can be fused with a therapeutic protein, including IL-2 through direct fusion or with one of the disclosed linkers. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claims 10-19 are rejected under 35 U.S.C. 103 as being unpatentable over Camu, W., et al (2020) Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): a phase 2a randomized, double-blind, placebo-controlled trial EBioMedicine 59(10844); 1-12 in view of
US 2007/0048282 A1 (Rosen, C.A., et al) 01 MAR 2007 and US 2014/0315817 A1 (Schmidt, M.M., et al) 23 Oct 2014.
Camu teaches that Amyotrophic Lateral Sclerosis (ALS) is a fatal neuromuscular disorder characterized by progressive muscle wasting and weakness (page 2, left column, paragraph 1). Camu teaches that CD4+FOXP3+ regulatory T cells (Tregs) physiologically regulate immune responses, contributing to the induction and maintenance of tolerance, thus preventing the onset of autoimmune and inflammatory diseases. Previous studies have shown that in ALS patients, decreased levels of Tregs were correlated with increased disease severity and were predictive of disease progression and survival, suggesting that they may be a potential target for therapy. Tregs are exclusively reliant on the cytokine interleukin 2 (IL-2) for their generation, activation, and survival. Low dose IL-2 (ld-IL-2) administration induces the selective expansion of Tregs in mice and human. Several clinical trials exploring the therapeutic potential of ld-IL-2 in auto-immune and inflammatory conditions have now been reported, showing feasibility and clinical safety of this approach. Building upon experience with ld-IL-2 in type-1 diabetes, Camu examined the safety and pharmacodynamic effects of ld-IL-2 in ALS through a phase-2a randomized double-blind, placebo controlled trial. The primary objective was to study whether immune and inflammatory parameters in ALS patients could be modified with low dose IL-2 therapy towards an improved tolerogenic state, with an acceptable safety profile (page 2, right column, paragraph 3).
Camu teaches that patients were treated with Proleukin® (aldesleukin) which was purchased in 22 MIU vials. Clinical trial unit preparation consisted of visually identical 1 ml polypropylene syringes containing 0.5 ml of either placebo or 1 MIU or 2 MIU of IL-2. Following randomization, patients started a 5-day cycle of once-daily subcutaneous injections which were repeated on weeks 5 and 9, for a total of 3 cycles per patients (page 3, 2.3. procedures). The trial profile provided by Camu teaches that the first administration cycle started on day 1, the second on day 29, and the third on day 57 (page 4, Fig. 1). It is noted that 1 MIU is equivalent to 106 IU.
Camu teaches that a significant, dose dependent increase in both absolute number and relative frequency of Tregs were observed in both the 2 MIU and 1 MIU groups. Comparing these results to those obtained in a double-blind clinical trial in individuals with type 1 diabetes, a similar magnitude of Treg response to ld-IL-2 was observed, with a ~1.5-fold increase in the Treg percentage of CD cells following 5 days of treatment with 1 MIU. Camu also notes that all individuals in both groups on active treatment showed an increase in Treg number and frequency and that no evidence of intrinsic impairment in Treg responsiveness to ld-IL-2 was found (page 9, right column, paragraph 3).
Camu also shows that the increase in Treg response was sustained over 4 weeks following a 5-day treatment cycle. This is important as optimum clinical efficacy is likely to require a sustained increase in Treg levels, and therefore potentially a continuous life-long treatment with ld-IL-2 (paragraph bridging pages 9-10).
Camu teaches that the findings suggest that in the ALS cohort tested, there was no loss of sensitivity to ld-IL-2 with repeated administration. Consistent with this and in agreement with other reports, it was observed that ld-IL-2 leads to a preferential increase in expression of CD25 on Tregs. This may increase sensitivity of Tregs to both administered and endogenous IL-2, thus potentially enhancing and sustaining treatment effect (page 10, left column, paragraph 2).
Camu also teaches that Treg function was assessed before and after IL-2 administration and results demonstrate that, overall, treatment with IL-2 results in both an increase in Treg frequency and in Treg suppressive function. This improvement in Treg function was highly significant in the 1 MIU arm, with all individuals showing an increase in function. This improvement of Treg function following ld-IL-2 treatment is consistent with previous observations in ALS that the suppressive function of Tregs among individuals with ALS could be improved by ex vivo expansion driven by recombinant IL-2 (page 10, left column, paragraph 3).
Camu further studied the effect of IL-2 on blood markers of ALS disease activity and teaches a significant and dose-dependent reduction in plasma concentration of CCL2, which drives leucocytes towards cites of neuroinflammation. Elevated CCL2 expression levels have been observed in neural tissue from individuals with ALS and are associated with infiltration and activation of macrophages and microglia. CCL2 levels in biological fluids are also elevated in ALS and correlate to disease score and survival, indicating CCL2 as a useful biomarker of disease activity (page 10, left column, paragraph 4).
Camu teaches that mechanisms underlying the polarization of myeloid cell activation states have also been proposed to harbor significant potential for intervening in the progression of neurological diseases, including ALS. In ALS models, an M1/inflammatory microglial phenotype characterizes end-stage disease phases and exerts neurotoxic activity with detrimental outcomes, while a shift to M2/immunoregulatory microglial phenotype has been shown to protect motor neurons. Interestingly, ld-IL-2 treatment was associated with a significant increase in CCL17 and CCL18, in keeping with a change in macrophage/microglial polarization towards an immunoregulatory/M2-like phenotype (paragraph bridging columns, page 10).
Camu concludes that ld-IL-2 was well tolerated and immunologically effective in subjects with ALS further supporting their investigation into their eventual therapeutic impact on slowing ALS disease progression (abstract).
Camu; however, does not disclose that the IL-2 is a fusion protein comprising hIL-2 and HSA with the structure recited in claim 1 or the pharmaceutical composition of claim 8.
The teachings of US’282 are as discussed in detail above and, as discussed in detail above, teaches the fusion protein of claim 1 as well as the pharmaceutical composition of claim 8.
US’282 further teaches that the albumin fusion proteins disclosed have higher plasma stability compared to the plasma stability of the same protein when not fused to albumin. Plasma stability refers to the time period between when the therapeutic protein is administered in vivo and carried into the bloodstream and when the therapeutic protein is degraded and cleared from the blood stream into an organ that ultimately clears the protein from the body. Plasma stability is measured in terms of the half-life of the protein (page 51, [0319]).
US’817 is discussed in detail above. As discussed above, US’817 teaches that HSA fusion enhances properties and that advantages of using a variant albumin serum in association with IL-2 includes extending the PK of the IL-2. The extended PK can have advantages; for example, the IL-2 can be administered less frequently and/or at reduced concentrations and/or more consistent delivery levels of IL-2 can be achieved (page 11, [0124] – page 12, [0127]).
It would have been prima facie obvious prior to the effective filing date of the claimed invention to substitute the IL-2 in the method of treating ALS disclosed by Camu with the IL-2 HSA fusion protein disclosed by US’282 and further motivated by US’817. An ordinarily skilled artisan would have been motivated to substitute the IL-2 with the IL-2 HSA fusion protein in order to increase the plasma stability of the IL-2 and/or its activity in solution in vitro and/or in vivo as disclosed by US’282 ([0009]). Additionally, US’817 teaches that the fusion of HSA can extend the PK of IL-2 providing advantages such as less frequent administration and/or reduced concentrations and/or more consistent delivery levels of IL-2. An ordinarily skilled artisan would have had a reasonable expectation of success as all of Camu, US’282, and US’817 teach IL-2 therapeutics.
Regarding claims 12 and 17, as discussed in detail above, Camu teaches administration of 1 MIU of IL-2, which is equivalent to 1 x 106 IU. This dosage is within the claimed range, rendering the claimed range obvious per MPEP 2144.05.
Furthermore, it would have been obvious to use the dosages studied by Camu as a starting point for routine optimization in order to determine the optimal dosage of the IL-2 HSA fusion protein, particularly where considerations were known in the art. For instance, as discussed in detail above, US’817 teaches that the addition of HSA to therapeutics, including IL-2, can extend the PK providing advantages including administration that is less frequent and/or at reduced concentrations.
MPEP 2144.05 (II) A. states "’[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)” and "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007)”.
Regarding claims 13 and 18, as discussed in detail above, Camu teaches administration of IL-2 in cycles on days 1, 29, and 57, which indicates administration every 28 days and meets administration every 7-28 days. It is noted that, while Camu performs injections daily for five days in each cycle, the administration of additional dosages still meets the instant claim limitations as the claimed method uses “comprising” language indicating the inclusion of unrecited elements or steps. See MPEP 2111.03 I.
Furthermore, it would have been obvious to use the dosing frequency studied by Camu as a starting point for routine optimization in order to determine the optimal frequency of the IL-2 HSA fusion protein, particularly where considerations were known in the art. For instance, as discussed in detail above, US’817 teaches that the addition of HSA to therapeutics, including IL-2, can extend the PK providing advantages including administration that is less frequent and/or at reduced concentrations. Additionally US’282 teaches that the fusion of HSA to IL-2 increases the plasma half-life of the IL-2 and, therefore, the circulation in the blood stream. See MPEP 2144.05 (II).
Non-Statutory 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 10-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/686,480 in view of Camu, W., et al (2020) Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): a phase 2a randomized, double-blind, placebo-controlled trial EBioMedicine 59(10844); 1-12.
App’480 claims a fusion protein of IL-2 and HSA that is the same as the instantly claimed invention (claims 1-9). App’480 further claims a method for treating or preventing inflammatory bowel disease (IBD) comprising administration of the fusion protein (claims 10 and 15). App’490claims that the fusion protein or pharmaceutical composition is administered orally or by injection, preferably subcutaneous or intravenous infusion (claims 12 and 17) and that the fusion protein is administered at 3x104 IU to 1x106 IU each dose (claims 13 and 18) and every 7-28 days, preferably every 14-28 days (claims 14 and 19).
The claims of App’480 differ from the instant claims in that App’480 claims methods of administering the fusion protein in the treatment of IBS while the instant claims are drawn to the treatment of ALS. The treatment of ALS with the fusion protein of App’480; however, would have been obvious prior to the effective filling date of the claimed invention.
The teachings of Camu are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to treat ALS in place of IBS in the method claimed in App’480 based on the teachings of Camu. It would have been obvious to treat ALS as Camu demonstrates that, in ALS, IL-2 treatment resulted in a significant increase in the % of Tregs following repeated cycles compared to a placebo as well as a dose dependent decrease in plasma CCL2, warranting investigation into the use of IL-2 in slowing ALS disease progression (abstract). An ordinarily skilled artisan would have had a reasonable expectation of success as App’480 teaches methods of treating disease with IL-2 HSA fusion proteins and Camu suggests that IL-2 can be used to treat ALS.
This is a provisional nonstatutory double patenting rejection.
Claims 1-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-23 of copending Application No. 18/686,504. Although the claims are not identical, they are not patentably distinct from each other.
App’504 claims an expression system characterized In that the expression system expresses a fusion protein of human interleukin 2 and human serum albumin, wherein the fusion protein comprises a human IL-2 or a variant thereof comprising an amino acid sequence set forth in SEQ ID NO: 1; an amino acid sequence set forth in SEQ ID NO: 1 having one or more amino acids substitution, deletion, and/or addition and while retaining equivalent functions; or an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1; and an HSA or a variant thereof, wherein the HSA or variant there of comprises: an amino acid sequence set forth in SEQ ID NO: 2; an amino acid sequence set forth in SEQ ID NO: 2 having one or more amino acids substitution, deletion, and/or addition and while retaining equivalent functions; or an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 2 (claim 11). App’504 further claims that the expression system is a CHO cell, preferably a CHO-K1 cell (claim 12) and that the fusion protein comprises SEQ ID NO: 1 and SEQ ID NO: 2 (claim 13). App’504 claims that the amino acid at position 125 of SEQ ID NO: 1 is not cysteine and is preferably substituted with serine or alanine (claim 14) and that the HSA and IL-2 is either directly linked or linked via a linker peptide where the linker peptide preferably is represented by a general formula (GnS)m, where n and m are an integer from 1 to 10 and, more preferably, n is an integer from 1 to 4 and m is an integer from 0 to 3 (claim 15). App’504 claims that the expression system has a signal peptide and that the fusion protein is encoded by a nucleotide sequence of SEQ ID NO: 3 (claims 16-18). App’504 claims that the fusion protein that is expressed has an amino acid sequence as set forth in SEQ ID NO: 4 (claim 19), which is identical to instant SEQ ID NO: 4. App’504 further claims the use of the expression system in the preparation of a medicament for the treatment of tumors, hepatitis, pneumonia, or immunodeficiency diseases (claim 20). App’504 further claims a fusion protein produced by the expression system and a method of treating tumors, hepatitis, pneumonia, or immunodeficiency diseases comprising administration of the fusion protein (claim 23).
The claims of App’504 differ from the instantly claimed invention in that App’504 claims an expression system that expresses the fusion protein. Additionally, the claims of App’504 include additional species of fusion proteins compared to the instantly claimed invention in that App’504 also encompasses a scope of the fusion protein in which SEQ ID NO: 1 and/or 2 have one or more amino acid substitutions, deletions, and/or additions while the instant claims are limited to the recited sequences or those with at least 90% identity to the recited sequences.
It would have been prima facie obvious to modify the claims of App’504 to include a fusion protein including that claimed by the instantly claimed invention as App’504 claims expression systems expressing fusion proteins encompassing the same structure as that instantly claimed and also claims fusion proteins produced by the expression system. Thus, one of ordinary skill in the art would have had a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Claims 8-9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-23 of copending Application No. 18/686,504 as discussed above and in view of US 2007/0048282 A1 (Rosen, C.A., et al) 01 MAR 2007. Although the claims are not identical, they are not patentably distinct from each other.
The claims of App’504 are as discussed in detail above.
The claims of App’504; however, do not include the fusion protein in a pharmaceutical formulation with a pharmaceutically acceptable carrier or that the dosage form is from those recited in claim 9.
The teachings of US’282 are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’504 to further include the fusion protein in a pharmaceutical formulation with a pharmaceutically acceptable carrier and to have the composition be in a dosage form for injection, including a solution or a lyophilized powder, and to include the carriers/excipients disclosed by US’282 in said formulation. It would have been obvious to include a pharmaceutical formulation and the dosage forms of US’282 as US’282 is also drawn to HSA fusion proteins and also teaches IL-2 – HSA fusion proteins. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claims 10-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-23 of copending Application No. 18/686,504 as discussed above and in view of Camu, W., et al (2020) Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): a phase 2a randomized, double-blind, placebo-controlled trial EBioMedicine 59(10844); 1-12.
The claims of App’504 are as discussed in detail above.
The claims of App’504 differ from the instant claims in that App’504 claims a method for the treatment of tumors, hepatitis, pneumonia, or immunodeficiency diseases. App’504 does not claim the instantly claimed method of treating ALS. The treatment of ALS with the fusion protein of App’504; however, would have been obvious prior to the effective filling date of the claimed invention.
The teachings of Camu are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to treat ALS in place of tumors, hepatitis, pneumonia, or immunodeficiency diseases in the method claimed in App’504 based on the teachings of Camu. It would have been obvious to treat ALS as Camu demonstrates that, in ALS, IL-2 treatment resulted in a significant increase in the % of Tregs following repeated cycles compared to a placebo as well as a dose dependent decrease in plasma CCL2, warranting investigation into the use of IL-2 in slowing ALS disease progression (abstract). An ordinarily skilled artisan would have had a reasonable expectation of success as App’504 teaches methods of treating disease with IL-2 HSA fusion proteins and Camu suggests that IL-2 can be used to treat ALS.
Regarding claims 12 and 17, as discussed in detail above, Camu teaches administration of 1 MIU of IL-2, which is equivalent to 1 x 106 IU. This dosage is within the claimed range, rendering the claimed range obvious per MPEP 2144.05. Furthermore, it would have been obvious to use the dosages studied by Camu as a starting point for routine optimization in order to determine the optimal dosage of the IL-2 HSA fusion protein, particularly where considerations were known in the art. For instance, as discussed in detail above, US’817 teaches that the addition of HSA to therapeutics, including IL-2, can extend the PK providing advantages including administration that is less frequent and/or at reduced concentrations.
See MPEP 2144.05 (II).
Regarding claims 13 and 18, as discussed in detail above, Camu teaches administration of IL-2 in cycles on days 1, 29, and 57, which indicates administration every 28 days and meets administration every 7-28 days. It is noted that, while Camu performs injections daily for five days in each cycle, the administration of additional dosages still meets the instant claim limitations as the claimed method uses “comprising” language indicating the inclusion of unrecited elements or steps. See MPEP 2111.03 I. Furthermore, it would have been obvious to use the dosing frequency studied by Camu as a starting point for routine optimization in order to determine the optimal frequency of the IL-2 HSA fusion protein, particularly where considerations were known in the art. For instance, as discussed in detail above, US’817 teaches that the addition of HSA to therapeutics, including IL-2, can extend the PK providing advantages including administration that is less frequent and/or at reduced concentrations. Additionally US’282 teaches that the fusion of HSA to IL-2 increases the plasma half-life of the IL-2 and, therefore, the circulation in the blood stream. See MPEP 2144.05 (II).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AUDREY L BUTTICE whose telephone number is (571)270-5049. The examiner can normally be reached M-Th 8:00-4:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached on 571-272-2911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
Prosecution Insights