DETAILED ACTION
Continued Examination Under 37 CFR 1.114
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04/09/2026 has been entered.
Notice of Pre-AIA or AIA Status
2. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims Status
3. Applicant’s amendments and remarks, filed 02/20/2026, are acknowledged. Claims 2, 5, 9, 11, 13 and 15 are cancelled. Claims 24-25 are new. Claims 1, 17, 19, 21, 22 and 23 are amended. As such, claims 1, 3 and 16-25 are pending examination and currently under consideration for patentability under 37 CFR 1.104.
Specification
4. It is noted that there are references on page 71 of the specification not disclosed in the information disclosure statement. If applicant wants the references considered, they must be on the IDS.
5. The use of the terms such as Zetasizer (page 67), 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. Applicant should review the specification for other trademarks and correction is required.
Withdrawn Rejections/Objections
4. The objection to the specification for title of the invention not being descriptive as set worth at page 4 of the previous Office action (mailed 08/20/2025) is withdrawn in view of the amended title.
5. The rejection of claim 11 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 pre-AIA the applicant regards as the invention matter as set forth at pp. 3-4 of the previous Office action (mailed 08/20/2025) is withdrawn in view of the cancelled claim.
6. The rejection of claim 17 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 pre-AIA the applicant regards as the invention matter as set forth at pp. 3-4 of the previous Office action (mailed 08/20/2025) is withdrawn in view of the amended claim.
7. The rejection of claim 19 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 pre-AIA the applicant regards as the invention matter as set forth at pp. 3-4 of the previous Office action (mailed 08/20/2025) is withdrawn in view of the amended claim
8. The rejection of claim 20 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 pre-AIA the applicant regards as the invention matter as set forth at pp. 3-4 of the previous Office action (mailed 08/20/2025) is withdrawn in view of the amended claim
9. The rejection of claim 22 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 pre-AIA the applicant regards as the invention matter as set forth at pp. 3-4 of the previous Office action (mailed 08/20/2025) is withdrawn in view of the amended claim
10. The rejection of claims 20 and 22 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 as set forth at page 5 of the previous Office action (mailed 08/20/2025) is withdrawn in view of the amended claims.
Maintained Rejections
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.
12. Claims 16 and 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 pre-AIA the applicant regards as the invention.
This rejection is maintained for reasons of record (pp. 3-4, Office action mailed 20 August 2025) and for the reasons discussed below. For convenience, the rejection is repeated herein, modified to the amended claims:
Claim 16 is indefinite for the recitation “wherein the aldesleukin/SDS aggregate distribution is measured by dynamic light scattering as shown in Fig. 2” because it is unclear what it is meant. For example, does such a limitation reference the measurement method or result in the figure, or both, or something else? The metes and bounds of the claim, therefore, cannot be determined. Further, in general, incorporation by reference to a specific figure or table is not permitted (with exception) (see MPEP 2173.05(s)). Claims 17 are similarly indefinite.
Applicant’s Arguments
Applicant’s arguments (page 2, remarks received 02/20/2026) have been fully considered but are not found to be persuasive for the following reasons. Applicant argues that incorporation by figure is permitted only in exceptional circumstances where there is no practical way to define the invention in words.
Response to arguments
This has been fully considered but is not found to persuasive. Examiner respectfully asserts that the reference to Figure 2 and 3 does not constitute an "exceptional circumstance" and must be conveyed in words so that the claims are complete in themselves as outlined in MPEP 2173.05(s). Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
13. Claims 16-19, 21 and 23 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112,
4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
This rejection is maintained for reasons of record (pp. 5-6, Office action mailed 20 August 2025) and for the reasons discussed below. For convenience, the rejection is repeated herein, modified slightly to address the amended claims’ limitation:
Claims 16-19, 21 and 23 recite “wherein the aldesleukin/SDS aggregate distribution is measured by dynamic light scattering ...”; and claims 21 and 23 recite “wherein the liquid pharmaceutical composition is stable and can be stored at 2-8 oC for a year” and “wherein the aldesleukin has a specific activity ranging between 16.6 and 19.5 IU/mg”; however, these limitations do not in any way further limit the methods of treatment of claim 1, respectively, from which claims 16-19 are dependent, respectively; i.e., such a limitation does not alter or relate to the active ingredient (the pharmaceutical composition of aldesleukin), method step, or patient population of the methods of treatment in the independent claims. Therefore, claims 16-19, 21 and 23 fail to further limit the subject matter of the claim upon which they depend.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Applicant’s Arguments
Applicant’s arguments (pp. 7-8, remarks received 20 February 2026) have been fully considered but are not found to be persuasive for the following reasons.
Applicant argues claim 19 is amended to further describe the subject recited in the method of claim 1. Applicant argues claim 16 further limits the active ingredient. Applicant argues claim 17, 18 and 21 are directed towards additional features of the active ingredient.
Response to Arguments
This has been fully considered but is not found to be persuasive for the following reasons. The method of treating does not require a stable storage temperature or measurements by dynamic light scattering. Applicant argues the limitations are directed towards features of the active ingredient, however, these limitations do not further limit the method of treatment of claim 1 as the limitation does not alter or relate to the activate ingredient, method step or the patient population.
Claim Rejections - 35 USC § 102/103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
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.
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.
14. Claims 1, 3, and 16-25 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Dorothee et al. (US 2016/0287671 A1, 10/6/2016), and as evidenced by Veerapathran et al. (US 2018/ 0127715 A1, 5/10/2018); and by Prometheus Laboratories Inc. (PROLEUKIN® (aldesleukin) drug label, 2012).
This rejection is maintained for reasons of record (pp. 7-9, Office action mailed 20 August 2025) and for the reasons discussed below. For convenience, the rejection is repeated herein, modified slightly to address the new and amended claims’ limitations:
Dorothee discloses that Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive loss of memory and cognitive functions, and accumulation of Aβ peptide is considered the initiating cause of pathogenic lesions; that Treg down regulate the ability of the neural tissue to resist to Aβ toxicity; that depletion of Tregs cells accelerated the onset of cognitive deficits in a mouse model of AD, the APPPS1 mice; and that administration of low doses of IL-2 in APPPS1 mice delayed the development of Alzheimer's disease and related disorders (page 1, [0002], [0005] and [0008], for example). Additionally, Dorothee teaches a method of treating Alzheimer's disease and related disorders by boosting Treg cells with a pharmaceutical composition comprising low dose IL-2 (abstract; page 1, [0009] - [0011] and [0013], for example). Further, Dorothee teaches that IL-2 is commercially available, including for pharmaceutical uses, and it is authorized for use in human patients, and examples of IL-2 include but are not limited to: Proleukin®, Aldesleukin®, Roncoleukin® (page 3, [0056]). Therefore, the reference anticipates claims 1 and 3. Further, as evidenced by Veerapathran, the amino acid sequence of aldesleukin comprises the sequence of SEQ ID NO: 4 (page 15, [0342]; and page 18, 2nd column, lines 4-6), which is 100% identical to the present SEQ ID NO: 1.
In addition, as evidenced by the PROLEUKIN® (aldesleukin) drug label, PROLEUKIN/ aldesleukin solution comprises SDS, mannitol, and monobasic and dibasic sodium phosphate (2nd page, 3rd paragraph).
With respect to the limitation “an aldesleukin pharmaceutical liquid composition-comprising SDS, mannitol, and a phosphate buffer” in the amended claim 1, and the limitation of “wherein aldesleukin is formulated as a liquid pharmaceutical composition comprising SDS, mannitol, and a phosphate buffer in the amended claim 11, as pointed out previously and above, as evidenced by the PROLEUKIN® (aldesleukin) drug label, PROLEUKIN/aldesleukin solution also comprises SDS, mannitol, and monobasic and dibasic sodium phosphate. In addition, with respect to the limitation “wherein aldesleukin and SDS form stable aldesleukin/SDS aggregates exhibiting ...” in claim 1, and the limitation “wherein ..., and aldesleukin and SDS form stable aldesleukin/SDS aggregates with ...” in claim 11, such would be inherent properties of the PROLEUKIN® (aldesleukin) composition of the prior art, which comprises the same ingredients as that recited in the present claims. Therefore, Dorothee still anticipates claims 1 and 3. Further, with respect to the limitation “wherein the aldesleukin/SDS aggregate distribution is measured by dynamic light scattering ...” in the amended claims 16-18; and the limitation “wherein the liquid pharmaceutical composition is stable and can be stored at 2-8 oC for a year” and “wherein the aldesleukin has a specific activity ranging between 16.6 and 19.5 IU/mg” in claims 21 and 23, as discussed above, they are not related to, or further limit the treatment methods of claims 1, respectively; therefore, make no difference. Therefore, Dorothee also anticipates claims 16-18, 21 and 23.
With respect to the limitation “wherein the subject has an immune disorder” in amended claim 19, and the limitation of “wherein the immune disorder is selected from the group consisting of multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, type 1 diabetes, systemic lupus, erythematosus, contact hypersensitivity, asthma, GVHD, Sjogren's Syndrome, cancer and an autoimmune disorder” in the amended claim 22, PROLEUKIN® disclose clinical studies of PROLEUKIN/aldesleukin solution efficacy was conducted in patient with metastatic renal cell carcinoma (page 3-4, clinical studies section).
With respect to the limitation “wherein the proliferation of regulatory T cells increase by at least 1-fold” in new claim 25, Dorothee discloses that “boosting of Treg cells refers to any increase in proportion of Treg cells relative to Teffs, in number or in activity as tested by suppressive assays or by expression of molecules that reflect the activity of the Tregs such as CD25, the alpha-chain of the IL-2 receptor, in a subject. The augmentation in proportion is preferably by at least 10%, 20%, 30%, 40%, 50%, 60% as compared to the level prior to treatment”. The 10-60% augmentation encompasses the increase of proliferation of reg Tcells by at least 1 fold.
Regarding the limitation, “wherein the liquid pharmaceutical composition contains 2.2 mg/ml aldesleukin” in amended claim 20 and “wherein the SDS is present at a concentration of 0.44 mg/ml and mannitol is present at a concentration of 50 mg/ml in the pharmaceutical liquid composition” in new claim 24, the Proleukin drug label teaches mannitol at 50 mg/ml. Regarding the other concentrations, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claims invention to perform the claimed method with the doses mannitol and SDS of the instant claims because one of skill in the art would have been motivated to optimize dosing to maximize efficacy and minimize side effects. Dorothee teaches the effective dosage can be adjusted by the practitioner, based on information contained in the present application. In particular, with the knowledge of the present invention that, in patients with Alzheimer's disorder, IL-2 may be administered under conditions that do activate Tregs without substantially activating Teff, the skilled person may be able to adjust dosages to each patient and condition (paragraph 73). Applicant is reminded that their disclosure presents a range for SDS at 0.0001mg/mL to about 10 mg/mL and aldesleukin in a range from about 0.001 mg to about 3 mg/mL, The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine the optimum dosage of a known agent to treat a disease. The determination of a dosing for any given drug is a matter of routine experimentation using well- established methods in the field, and can be reasonably expected to produce predictable results. Further, optimizing dosing to achieve a desired clinical result is obvious because dosage and dosing frequency are art recognized result effective parameters in the pharmaceutical/medical arts.
In the alternative, while as evidenced by the drug label, PROLEUKIN® (aldesleukin) comprises the same ingredients as claimed, the prior art is silent about the aldesleukin/SDS aggregates, and examiner is unable to determine whether the prior art disclosure possesses the non-recited property. With these conditions, where the prior art PROLEUKIN® (aldesleukin) composition comprises the ingredients that seem to meet the limitations of the composition of claims 1, except that the prior art is silent to the aldesleukin/SDS aggregates as claimed, then the burden shifts to the applicant to provide evidence that the prior art would neither anticipate nor render obvious the claimed invention. Note the case law of In re Best 195 USPQ 430, 433 (CCPA 1977).
Claims 1, 3, and 16-25 are rejected under 35 U.S.C. 102(a(1)) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Dorothee et al. (US 10,183,061, 1/22/2019), and as evidenced by Veerapathran et al. (US 2018/ 0127715 A1, 5/10/2018); and by Prometheus Laboratories Inc. (PROLEUKIN® (aldesleukin) drug label, 2012), for the same reasons above as it is the patent of US 2018/ 0127715 application. See also the claims in the ‘061 patent.
Claims 1, 3, and 16-25 are rejected under 35 U.S.C. 102(a(1)) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Clinical Trial NCT02059759 (6/1/2016), and as evidenced by Veerapathran et al. (US 2018/ 0127715 A1, 5/10/2018); and by Prometheus Laboratories Inc. (PROLEUKIN® (aldesleukin) drug label, 2012), for similar reasons above.
Applicant’s Arguments
Applicant’s arguments (pp. 9-14, remarks received 02/20/2026) have been fully considered but are not found to be persuasive for the following reasons.
Applicant argues that the PROLEUKIN® drug label is different from the liquid composition taught by Applicant. Although the PROLEUKIN® drug label contains the same components as the inventive liquid pharmaceutical composition, the aldesleukin behaves differently in the inventive liquid composition due to the different measurements in dynamic light scattering. Applicant argues that the size/distribution of the aldesleukin/SDS aggregates in the PROLEUKIN® composition is different from the aggregates taught by the inventive liquid composition.
Response to arguments
This has been fully considered but is not found to be persuasive. As stated above in the 35 U.S.C. 112(d) rejection, the limitation of the aggregates measured by dynamic light scattering do not contribute to the method of treating. This limitation does not alter or relate to the active ingredient (the pharmaceutical composition of aldesleukin), method step, or patient population of the methods of treatment in the independent claims. Applicant argues that the aggregate size distribution difference renders the PROLEUKIN® drug label different from the inventive liquid pharmaceutical composition, however, the prior art teaches the same composition and the aggregate size distribution follows inherently. The dynamic light scattering characterization is a quality control parameter, not a method limitation. Applicant states in the remarks filed 02/20/2026 that the PROLEUKIN® drug label teaches the same components at the same concentrations as the inventive liquid pharmaceutical composition, however, claims that the aldesleukin behaves different. If the same components at the same concentration are taught, then the properties that are exhibited by the prior art liquid composition would be identical to the inventive liquid composition. Thus, the rejection is maintained as both the prior art liquid composition and inventive liquid composition are identical.
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
15. Claims 1, 3, and 16-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 12, 14-17, 19 and 22 of copending Application No. 18/344,130, in view of Clinical Trial NCT02059759 (6/1/2016), for the reasons of record set forth in the last previous Action mailed on 1/28/2025, at page 7.
The previous rejection is stated herein, modified slightly to incorporate the new amendments.
Claims 12, 14-17, 19 and 22 of the ‘130 application are directed to a liquid pharmaceutical composition comprising aldesleukin/SDS microaggregates comprising a specific activity from 0.1 million IU/mg up to 20 million IU/mg and an aldesleukin/SDS microaggregate distribution in the liquid composition at least for a year in the range of 4 - 18 nm range with a peak at about 8 nm as measured by dynamic light scattering (claim 1 (and the dependent claims), for example); or a liquid composition comprising: SEQ ID NO: 1, in a range from about 0.001 mg/ml to about 3 mg/ml, sodium dodecyl sulfate (SDS) in a range from about 0.05 mg/ml to about 20 mg/ml, osmolytes (claims 17 and 19, for example). The SEQ ID NO: 1 of the ‘915 Application is 100% identical to the present SEQ ID NO: 1. The teachings of Clinical Trial NCT02059759 (6/1/2016) are reviewed above (under “Prior Art Rejection”). It would have been obvious to the person of ordinary skill in the art to treat a neurodegenerative disorder such as ALS with the liquid pharmaceutical composition claimed in the ‘130 Application by promoting Treg proliferation, in view of the teachings of NCT02059759. Therefore, the conflicting claims are not patentably distinct from each other for the reasons discussed above. See also Sun Pharmaceutical Industries, Ltd. v. Eli Lilly and Company (Fed. Cir. July 28, 2010).
Applicant’s Arguments
Applicant requests that the rejection be held in abeyance until allowable subject matter is identified.
Response to Arguments
This has been fully considered but is not found to be persuasive. Applicant’s attention is respectfully directed to M.P.E.P. § 804(I)(B)(1), which states:
A complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (see MPEP § 1490 for a discussion of terminal disclaimers). Such a response is required even when the nonstatutory double patenting rejection is provisional.
As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance. Only objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated. Replies with an omission should be treated as provided in MPEP § 714.03.Therefore, an application must not be allowed unless the required compliant terminal disclaimer(s) is/are filed and/or the withdrawal of the nonstatutory double patenting rejection(s) is made of record by the examiner. See MPEP § 804.02, subsection VI, for filing terminal disclaimers required to overcome nonstatutory double patenting rejections in applications filed on or after June 8, 1995. (emphasis added)
Accordingly, the rejection is maintained and is expressly not held in abeyance.
New Objection/ Rejections Necessitated by Amendments
Claims Rejections
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
11. First, claim 1 and 3 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. Please note claim 1 is included in this rejection because it is the claim that claim 3 depends upon. 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 MPEP states that the purpose of the written description requirement is to ensure
that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. 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.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
The instant claims drawn to the method of claim 1, wherein the aldesleukin comprises SEQ ID NO: 1 or a variant there of.
The specification teaches that the IL-2 molecules herein include IL-2 variants of the present disclosure comprising an amino acid sequence that has at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the IL-2 amino acid sequence (SEQ ID NO: 1) (page 3).
The issue with regard to the written description provision is that the genus of variant is not adequately described. The claims also broadly encompass variant. The specification provides no guidance regarding which amino acids can be modified in the variant, while maintaining any given function. Therefore, these structures (i.e., different forms) are claimed only be their functional characteristics and the specification fails to provide sufficient correlation between the claimed functional characteristics and the necessary structural components (i.e., critical domains within the sequences).
Furthermore, Applicants have not shown possession of a representative number of species that have the claimed function(s). While the specification clearly sets forth a correlation between the claimed variant, and the claimed functions, this correlation does not appear to be clearly present in the breadth of the claims. As noted above, the claims are not limited to the disclosed variant. Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. There is no description of the structure common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Therefore, only one species has been described and this is not considered to be representative of the breadth of the genus. Therefore, given the lack of structure function correlation and the lack of a representative number of species, the specification provides insufficient written description to support the genus encompassed by the claim.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed variant, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481,1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does 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 1966.
Protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Punta et al. (PLoS Comput Biol 4(10): e1000160, 2008) teach that homology (both orthology and paralogy) does not guarantee conservation of function (See page 2). Punta et al. teach that relatively small difference in sequence can sometimes cause quite radical changes in functional properties, such as a change of enzymatic action, or even loss or acquisition of enzymatic activity itself (See page 2). Punta et al. teach that it is also apparent that there is no sequence similarity threshold that guarantees that two proteins share the same function (see page 2). Punta et al. teach that homology between two proteins does not guarantee that they have the same function, not even when sequence similarity is very high (including 100% sequence identity) (See page 2 and table 2). Punta et al. teach that proteins live and function in 3D, and therefore structural information is very helpful for predicating function (See page 4). However, as with sequence, two proteins having the same overall architecture, and even conserved functional residues, can have unrelated functions (See page 4). Punta et al. teach that still; structural knowledge is an extremely powerful tool for computational function prediction (See page 5).
Similarly, Whisstock et al. (Quarterly Reviews in Biophysics. 36(3):307-340, 2007) teach that the prediction of protein function from sequence and structure is a difficult problem (See abstract). Although many families of proteins contain homologues with the same function, homologous proteins often have different functions as the sequences progressively diverge (See page 309). Whisstock et al. teach that moreover, even closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function (See page 309). Further, Whisstock et al. note that in some instances, even sequences that are the same can have different functions. For example, eye lens proteins in the suck are identical in sequence to active lactate dehydrogenase and enolase in other tissues, although they do not encounter the substrates in the eye (See page 310). Whisstock et al. teach that assigning a function to an amino acid sequence based upon similarity becomes significantly more complex as the similarity between the sequence and a putative homologue fall (See page 321). Whisstock et al. teach that while it is hopeful that similar proteins will share similar functions, substitution of a single, critically placed amino acid in an active-site may be sufficient to alter a protein’s role fundamentally (See pages 321-323).
The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Song et al. (Molecular Biology of the Cell, 15:1287–1296, March 2004) who teach that substitution of alanine for aspartate in surviving results in the conversion of surviving’ apoptotic function from anti-apoptotic to proapoptotic and changes in its subcellular localization (See page 1287-1289). Moreover, Defeo-Jones et al. (Molecular and Cellular Biology, Sept. 1989, p. 4083-4086) teach that the conservative substitution of lysine for arginine at position 42 completely eliminated biological activity (See abstract and pages 4084-4085). These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Additionally, Bork (Genome Research, 2000; 10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
Given not only the teachings of Punta et al., Whisstock et al., Song et al., Burgess et al., and Defeo-Jones et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed proteins having the required function(s) could not be predicted based on sequence identity. Clearly, it could not be predicted that polypeptide or a variant that shares only partial homology with a disclosed protein will function in a given manner. Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the proteins per se and thereby does not provide adequate written description support for which structural features of any given polypeptide would predictably retain their functional activities.
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen- Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does 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 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, ‘does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the “written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed. Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Second, claim 22 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 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.
Claim 22 is drawn to the method of claim 19, wherein the immune disorder is selected from the group consisting of multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, type 1 diabetes, systemic lupus, erythematosus, contact hypersensitivity, asthma, GVHD,Sjogren's Syndrome, cancer and an autoimmune disorder.
The specification teaches "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Included in this definition are benign and malignant cancers as well as dormant tumors or micrometastatses (page 11). The specification teaches examples of cancer include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include squamous cell cancer, lung cancer (including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancer, as well as B-cell lymphoma (including low grade/follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade15 diuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome (page 11)
A immune disorder that is cancer does not meet the written description provision of 35 U.S.C. 112, first paragraph. The claims broadly encompass treating all cancers using the aforementioned method. The claims broadly encompass the use the liquid pharmaceutical composition to induce reg T cell proliferation in subjects with all cancers; however, the specification does not demonstrate that the liquid pharmaceutical composition has the function of treating all cancers. Therefore, the method has no correlation with its function. The specification is not deemed sufficient to reasonably convey to one skilled in the art that the inventors, at the time the invention was made, had possession of a method of treating all cancers with the claims method because the genus encompasses conditions which differ from those disclosed in etiologies, molecular mechanisms, diagnostic approaches, treatment modalities, and therapeutic endpoints. Furthermore, the recited genus encompasses conditions yet to be discovered and/or characterized; therefore, the skilled artisan cannot envision preventing all the contemplated diseases encompassed by the instant claims. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does 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 1966.
A "representative number of species" means that the species, which are adequately described, are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]. "See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) "[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
Regarding the vast genus of cancers encompassed by the claims, while the state of the art is relatively high with regard to the treatment of specific cancer types, the state of the art with regards to treating all cancers with a single treatment is underdeveloped. In particular, there is no known combination of interferon and anticancer agent that is effective against all cancer cell types. The cancer treatment art involves a very high level of unpredictability. Heppner et al. (Cancer Metastasis Review 2:5-23; 1983) discuss the heterogeneity of tumors from different tissues, as well as the same tissue. A key point made by Heppner et al. is that tumor heterogeneity contributes greatly to the sensitivity of tumors to drugs. Heppner et al. teach that as a tumor progresses to a metastatic phenotype, the susceptibility to a particular treatment can differ, and as such, makes predicting the responsiveness to treatment difficult. Additionally, Bally et al. (US Patent No. 5,595,756) stated, "Despite enormous investments of financial and human resources, no cure exists for a variety of diseases. For example, cancer remains one of the major causes of death. A number of bioactive agents have been found, to varying degrees, to be effective against tumor cells. However, the clinical use of such antitumor agents has been highly compromised because of treatment limiting toxicities (See column 1). Sporn et al. (Chemoprevention of Cancer, Carcinogenesis, Vol. 21 (2000), 525-530) teaches the magnitude of mortality of cancers and that mortalities are in fact still rising and that new approaches to a variety of different cancer are critically needed. Sporn et al. also teach that “given the genotype and phenotype heterogeneity of advanced malignant lesions as they occur in individual patients, one wonders just exactly what are the specific molecular and cellular targets for the putative cure.”
Furthermore, the art indicates the difficulties in going from in vitro to in vivo for drug development for treatment of cancers. Auerbach et al. (Cancer and Metastasis Reviews, 2000, 19: 167-172) indicate that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response. For example, the 96 well rapid screening assay for cytokinesis was developed in order to permit screening of hybridoma supernatants…In vitro tests in general have been limited by the availability of suitable sources for endothelial cells, while in vivo assays have proven difficult to quantitate, limited in feasibility, and the test sites are not typical of the in vivo reality (see p. 167, left column, 1st paragraph). Gura T (Science, 1997, 278(5340): 1041-1042) indicates that “the fundamental problem in drug discovery for cancer is that the model systems are not predictive at all” (see p. 1, 2nd paragraph). Furthermore, Gura T indicates that the results of xenograft screening turned out to be not much better than those obtained with the original models, mainly because the xenograft rumors don’t behave like naturally occurring tumors in humans—they don’t spread to other tissues, for example (see p. 2, 4th paragraph). Further, when patient’s tumor cells in Petri dishes or culture flasks and monitor the cells’ responses to various anticancer treatments, they don’t work because the cells simply fail to divide in culture, and the results cannot tell a researcher how anticancer drugs will act in the body (see p. 3, 7th paragraph). Furthermore, Jain RK (Scientific American, July 1994,58-65) indicates that the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate and brain (see p. 58, left most column, 1st paragraph). Further, Jain RK indicates that to eradicate tumors, the therapeutic agents must then disperse throughout the growths in concentrations high enough to eliminate every deadly cells…solid cancers frequently impose formidable barriers to such dispersion (see p. 58, bottom of the left most column continuing onto the top of the middle column). Jain RK indicates that there are 3 critical tasks that drugs must do to attack malignant cells in a tumor: 1) it has to make its way into a microscopic blood vessel lying near malignant cells in the tumor, 2) exit from the vessel into the surrounding matrix, and 3) migrate through the matrix to the cells. Unfortunately, tumors often develop in ways that hinder each of these steps (see p. 58, bottom of right most column). Thus, the art recognizes that going from in vitro studies to in vivo studies for cancer drug developments are difficult to achieve.
Hait (Nature Reviews/Drug Discovery, 2010, 9, pages 253-254) states that “The past three decades have seen spectacular advances in our understanding of the molecular and cellular biology of cancer. However, with a few notable exceptions, such as the treatment of chronic myeloid leukaemia with imatinib, these advances have so far not been translated into major increases in long-term survival for many cancers. Furthermore, data suggest that the overall success rate for oncology products in clinical development is -10%, and the cost of bringing a new drug to market is over US$1 billion.” (see page 253, left column, the 1st paragraph). Hait further teaches “The anticancer drug discovery process often begins with a promising target; however, there are several reasons why the eventual outcome for a particular cancer target may be disappointing. For example, the role of the target in the pathogenesis of specific human malignancies may be incompletely understood, leading to disappointing results”, “First, many targets lie within signal transduction pathways that are altered in cancer, but, owing to the complex nature of these pathways, upstream or downstream components may make modulating the target of little or no value”; “Second, target overexpression is often overrated. There are some instances in which overexpression predicts response to treatment.”; and “Another confounding factor is that cancer is more than a disease of cancer cells, as alterations in somatic or germline genomes, or both, create susceptibilities to transformational changes in cells and in the microenvironment that ultimately cooperate to form a malignant tissue. The putative role of cancer stem cells in limiting the efficacy of cancer therapeutics is also an area of intense interest. Therefore, effective treatments may require understanding and disrupting the dependencies among the multiple cellular components of malignant tissues. Single nucleotide polymorphisms in genes responsible for drug metabolism can further complicate the picture by affecting drug pharmacokinetics; for example, as with the topoisomerase inhibitor irinotecan.”, for example, page 253, Section “Understanding the target in context”. Hait also teaches “Drug effects in preclinical cancer models often do not predict clinical results, as traditional subcutaneous xenografting of human cancer cell lines onto immunocompromised mice produces ‘tumours’ that fail to recapitulate key aspects of human malignancies such as invasion and metastasis. Several improvements have been made, including orthotopic implantation and use of mice with humanized haematopoietic and immune systems. Newer genetic mouse models can also allow analyses of tumour progression from in situ through locally advanced and, in certain cases, widespread metastatic disease. However, whether or not these models will more accurately predict drug activity against human cancer remains to be determined. Other alternatives, including three-dimensional tissue culture or xenografts of fresh human biopsy specimens onto immunocompromised mice, have the potential advantage of including the human microenvironment. However, these approaches have yet to prove their value relative to their cost.”, for example, page 253, Section “Predictive models”. Furthermore, Hait teaches that “It is now widely thought that biomarkers will drive a personalized approach to cancer drug development. The aim is that they will cut costs, decrease time to approval, and limit the number of patients who are exposed to potential toxicities without a reasonable chance of benefit — as exemplified by the development of imatinib and trastuzumab. However, recent attempts at repeating these successes in other cancer types have been less successful.”, for example, page 254, Section “Stratified/personalized medicine”. The challenges facing cancer drug development are further confirmed and discussed in Gravanis et al (Chin Clin Oncol, 2014, 3, pages 1 -5). Gravanis et al teach “The generic mechanism of action for cytotoxics made the prediction of which tumor types might respond to them very difficult, if not impossible, and necessitated a ‘trial and error’ approach against many different types of tumors.” and “The most prominent change in oncology drug development in the last 20 years has been the shift from classic cytotoxics to drugs that affect signaling pathways implicated in cancer, which belong to the so called ‘targeted therapies’.”, for example, page 1, Section “From cytotoxics to targeted therapies: how far are we from truly personalized medicine?”. Gravanis et al. further teach “Although constantly progressing, an understanding of cancer biology is far from complete. The ability to develop new compounds or generate biological data predictive of the clinical situation relies on good quality basic research data, although the complexity and constantly evolving biology of the tumor may be to blame for the frequent non-reproducibility of research results. Systemic biology approaches of the -omic type still generate largely incomprehensible, mostly due to their volume, analytical data, few pieces of which are currently actionable/drug-g-able. Finally, animal models of cancer are similarly unable to predict the clinical situation (for example, page 3, right column, the 2nd paragraph).
Beans (PNAS 2018; 115(50): 12539-12543) teaches that across cancer types, 90% of cancer deaths are caused not by the primary tumor but by metastasis. Beans teaches that although some drugs may shrink metastases along with primary tumors, no existing drugs treat or prevent metastasis directly (See page 12540). Beans states “Without a targeted approach, metastatic tumors often reemerge. “We shrink them, we send them back to their residual state, and they reenact those survival functions and retention of regenerative powers that made them metastasis-initiating cells in the first place” (See page 12540). Beans teaches that one of the major scientific challenges of studying metastatic disease is that different forms of cancer seem to metastasize through different mechanisms and the same form of cancer may metastasize differently in different subsets of patients (See page 12542). Of note, Beans states “It’s unlikely that one researcher is going to find one pathway that proves to be the key to metastasis” (See page 12542). Bean also teaches that translating many findings into therapies also presents unique hurdles in that it is difficult to measure the effectiveness of the therapy. Secondary tumors are often minuscule, and therefore, measuring success by tumor shrinkage may not work. Measuring the incidence of metastasis after treatment is also more difficult (See page 12542).
Given Bally et al teaching of treatment-limiting toxicities in clinical use; Sporn's teaching that the cancer progression is heterogeneous as it progresses, both in genotype and phenotype; Auerbach et al teaching that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response; Gura's teaching that the models are unpredictable; Jain's teaching that the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate and brain; both Hait and Gravanis et al teaching various challenges facing cancer drug development, such as an understanding of cancer biology is far from complete, drug effects in preclinical cancer models often do not predict clinical results and many others; and Beans teachings that the field is highly underdeveloped with regards to preventing and treating cancer metastasis; the cited references demonstrate that the treatment of cancer is highly unpredictable, if even possible for many cancers.
The prior art does not teach any combination of mannitol, phosphate buffer, aldesleukin and SDS can induce proliferation of reg T cell for subjects with all cancers, and therefore, it is unclear if the claimed method would have the claimed function. Accordingly, one of skill in the art would conclude that the claimed invention encompasses a broad genus of cancers that may not respond to treatment with the claimed method. It should be noted that the specification has not demonstrated treating all cancers with the claimed method. Based on the teaching of the instant specification and the prior art one of skill in the art would not conclude that Applicant was in possession of the claimed method of treating the genus of cancers.
Consequently, the method for inducing proliferation of reg T cell in subjects with all cancers comprising administering the liquid pharmaceutical composition does not meet the written description provision of 5 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The applicant has not disclosed any species representative of the genus, which is highly variant. Applicant is reminded that Vas- Cath makes clear that the written description provision of 5 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is severable from its enablement provision. (See page 1115).
Conclusion
16. No claims are allowed.
17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Syed J Abbas whose telephone number is (571)272-0015. The examiner can normally be reached M-Th, 9:00AM-4:00PM.
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/SYED J ABBAS/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674
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