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 .
Priority
The present application, filed September 29, 2023, is a national stage application of PCT/JP2022/009524, filed March 4, 2022, and claims priority to foreign priority application JP2021-057101, filed March 30, 2021.
Status of the Application
Applicant’s preliminary amendment, received April 12, 2024, is acknowledged.
Claims 11-19 are pending in this application and examined on the merits herein.
Claim Interpretation
The present specification states: "D-allose and/or a derivative thereof, and/or a mixture
thereof'' may also be shortened to simply "D-allose" (p. 10, lines 32-33). Therefore, the limitation “D-allose” as recited in claim 11 is interpreted to include D-allose and/or a derivative thereof and/or a mixture thereof, as defined in the specification.
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.
Claims 11-19 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 a method for treatment a disease associated with cytokine overproduction in a subject, does not reasonably provide enablement for a method for prevention of a disease associated with cytokine overproduction in a subject. 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.
The Applicant’s attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
Nature of the invention: The present invention is drawn to a method for treatment or prevention of a disease associated with cytokine overproduction in a subject, comprising: administering a cytokine production suppressing composition containing D-allose as the active ingredient, to the subject in need thereof.
With respect to the definition of “prevention”, the claims are given their broadest reasonable interpretation.
The Oxford English Dictionary defines the verb “to prevent” as “to preclude the occurrence of (an anticipated event, state, etc.); to render (an intended, possible, or likely action or event) impractical or impossible by anticipatory action; to put a stop to” (p. 8, definition II.9.a of “prevent”; cited in PTO-892). “Preventing” as recited in the instant application is thus interpreted to mean the complete and total blocking of all diseases associated with cytokine overproduction in a subject for an indefinite period of time. Merely making diseases associated with cytokine overproduction in a subject less likely or less severe would not render the disease impossible and thus not qualify as preventing.
The state of the prior art: As one example of a disease associated with cytokine overproduction, Fajgenbaum (Fajgenbaum, D. C.; et al. The New England Journal of Medicine 2020, vol. 383, pp. 2255-2273; cited in PTO-892) teaches cytokine storm and cytokine release syndrome are life-threatening systemic inflammatory syndromes involving elevated levels of circulating cytokines and immune-cell hyperactivation that can be triggered by various therapies, pathogens, cancers, autoimmune conditions, and monogenic disorders (p. 2255, first paragraph, lines 9-13). Therefore, one of ordinary skill in the art would have recognized cytokine storm and cytokine release syndrome as diseases associated cytokine overproduction that may be caused by a triggered by a wide range of conditions.
As a second example of a disease associated with cytokine overproduction, Galdiero (Galdiero, M. R.; et al. Cold Spring Harbor Perspectives in Biology 2018, 10:a028662; cited in PTO-892) teaches there is compelling evidence that cellular and humoral components of the tumor microenvironment have a large impact on cancer initiation and progression and on the resilience of most tumors in the face of therapy. Galdiero teaches that macrophages and neutrophils are both integrated within cancer-related inflammation and can take part in the various phases of tumor initiation and progression, and that cancer cells, tumor-associated macrophages, and neutrophils can release a plethora of protumorigenic and proangiogenic cytokines/chemokines p. 11, left column, Concluding Remarks, lines 11-14)
Galdiero teaches that targeting these mediators as well as blocking protumor
functions could be useful for inhibiting tumor growth (p. 11, left column, Concluding Remarks, lines 11-14). However, Galdiero does not teach or suggest that suppressing levels cytokines related to tumor progression may render tumor formation or tumor growth impossible.
Finally, Ueki 2008 (Ueki, M.; et al. Journal of Bioscience and Bioengineering 2008, vol. 105, pp. 481-485; cited in PTO-892) teaches a study to examine the effects of D-allose on renal injury in the systemic inflammatory response induced by LPS administration, with an emphasis on systemic TNF-alpha and the activation of neutrophils in the rat kidney. Ueki 2008 teaches that serum and renal TNF-alpha, renal cytokine-induced neutrophil chemoattractant (CINC)-1, and myeloperoxidase (MPO) concentrations were evaluated and that administration of D-allose inhibited LPS-induced increases in serum and renal TNF-alpha concentrations and in renal CINC-1 and MPO concentrations after LPS administration (p. 481, Abstract, lines 5-12). Specifically, Ueki 2008 teaches that changes in serum TNF-alpha concentration 1 h after LPS administration were reduced by administration of 400 mg/kg D-allose (p. 482, Figure 1). However, Ueki shows that the dose of 400 mg/kg D-allose reduces the levels of TNF-alpha relative to the LPS sample, but does not restore levels of TNF-alpha to that observed in rats not treated with LPS (p. 482, Figure 1).
Therefore, in view of the prior art, one of ordinary skill in the art would not have reasonably expected that all cytokine-associated diseases may be prevented by administering a composition comprising D-allose. Moreover, in view of Ueki 2008 teaching a reduction in TNF-alpha levels after administration with D-allose but not restoration of TNF-alpha levels to that observed in mice not treated with LPS, one of ordinary skill in the art would not have reasonably predicted that administration of D-allose would prevent all diseases associated with cytokine overproduction, such as sepsis.
Moreover, prevention of a disease of a disease or disorder is not the same as treatment of
said disease or disorder. In order to prevent a disease, as opposed to merely delaying or reducing
symptoms, a method must either render the subject completely resistant to said disease after a
limited number of treatments, or, when continued indefinitely, continue to suppress the
occurrence of that disease. The prior art does not provide an expectation that the administration
of a composition comprising D-allose will render diseases associated with cytokine overproduction in a subject impossible by anticipatory action.
The relative skill of those in the art: The relative skill of those in the art is high.
The predictability or unpredictability of the art: The lack of prior art disclosing a
prevention for all diseases associated with cytokine overproduction means that one skilled in the art cannot predict the usefulness of a product or method to make these conditions possible. In addition, because Fajgenbaum teaches cytokine storm and cytokine release syndrome can be triggered by many different factors, including various therapies, pathogens, cancers, autoimmune conditions, and monogenic disorders, one of ordinary skill in the art would have found a claim that administration of D-allose or a derivative thereof may prevent, for example, cytokine release syndrome triggered by any of the above factors, to be unpredictable.
Moreover, because Ueki 2008 teaches that mice treated with LPS and D-allose still show an increase in TNF-alpha levels relative to mice not treated with LPS, one of ordinary skill in the art would have found a claim that administration of D-allose or a derivative thereof can prevent diseases associated with cytokine production to be unpredictable.
The breadth of the claims: The claims include a method for treatment or prevention of any disease associated with cytokine overproduction in a subject by administering a cytokine production suppressing composition containing D-allose as the active ingredient, to the subject in need thereof.
The term prevention is defined as described in the above Nature of the Invention section.
The amount of direction or guidance presented: The specification provides that plasmacytoid dendritic cells can produce high amounts of type I interferon (p. 1, lines 18-22), and augments a biological defense during viral infection (p. 1, lines 24-25). The specification further provides that in autoimmune diseases such as systemic lupus erythematosus (SLE) or psoriasis vulgaris, complexes comprising patient-derived nucleic acids and proteins activate
plasmacytoid dendritic cells, inducing high production of type I interferon, which elicits activation of immunocytes accelerating production of autoantibodies and is thought to further lead to reactivation of plasmacytoid dendritic cells (p. 1, lines 25-32). The specification suggests that this cycle of reactivation of plasmacytoid dendritic cells may be interrupted by production of type I interferon by plasmacytoid dendritic cells p. 1, lines 35-36).
The presence or absence of working examples: The specification provides working examples of treatment of conventional dendritic cells and plasmacytoid dendritic cells isolated from mice spleen cells with D-allose in cell culture. Specifically, the specification provides that these cells were treated with a TLR7 (polyuridylic acid) or TLR 9 ligand (CpG DNA) to stimulate cytokine production, and the levels of interferon-α (IFN- α) and interleukin-12 (IL-12) in the culture supernatant were measured (p. 14, lines 20-22). The specification provides that when D-allose was included in the medium instead of D-glucose, cytokine production accompanying the stimulation was found to be notably attenuated, but when D-allulose, L-allulose, D-glucose or D-fructose was used, attenuation of cytokine production was not observed (p. 14, lines 22-25; results in Figure 2).
The specification further provides the cDC subset of dendritic cells produce IL-12 after CpG DNA stimulation, but that IL-12 production was not lowered even when D-allose was included in the medium (p. 14, lines 27-29; results in Figure 3). In addition, the specification provides that macrophages in the intraperitoneal region of mice produce TNF-α upon lipopolysaccharide (LPS) stimulation, simultaneously producing nitric oxide, and this response was not attenuated whether including D-allose, D-allulose, L-allulose or D-fructose in the medium (p. 14, lines 29-32).
Note that lack of working examples is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art such as prevention of diseases associated with cytokine overproduction. See MPEP 2164.
The quantity of experimentation necessary: In order to practice the invention with the full range of all possible methods of treatment beyond those known in the art, one of ordinary skill in the art would be required undertake a novel and extensive research program into the treatment of diseases associated with cytokine overproduction. Because this research would have to be exhaustive, and because it would involve a wide scope of diseases associated with cytokine overproduction for which there is no single cause or mechanism of disease, and because one may be required to develop a new model to definitively show that diseases associated with cytokine overproduction are successfully prevented by administration of D-allose, it would constitute an undue and unpredictable search burden.
Genentech, 108 F.3d 1361 at 1366, states that, “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion.” And “patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.”
Therefore, in view of the Wands factors, as discussed above, particularly the breadth of the claims and nature of the invention, Applicants fail to provide information sufficient to practice the claimed invention for preventing diseases associated with cytokine overproduction in a subject comprising administering a cytokine production suppressing composition containing D-allose to a subject in need thereof.
Claims 11-19 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 a method for treatment of collagen
disease, joint inflammation, muscular inflammation, chronic rheumatoid arthritis, rheumatoid
spondylitis, osteoarthritis, uric acid arthritis, skin inflammation, eczema, systemic
lupus erythematosus, glomerular nephritis, lupus nephritis or membranous nephritis, Sjogren's syndrome, psoriasis, ischemia/reperfusion, sepsis, and non-alcoholic fatty liver disease, does not reasonably provide enablement for a method for treatment of all diseases associated with cytokine overproduction. 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.
The Applicant’s attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
(1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
Nature of the invention: The present invention is drawn to a method for treatment of a disease associated with cytokine overproduction in a subject, comprising: administering a cytokine production suppressing composition containing D-allose as the active ingredient, to the subject in need thereof.
State of the prior art: Fajgenbaum (Fajgenbaum, D. C.; et al. The New England Journal of Medicine 2020, vol. 383, pp. 2255-2273; cited in PTO-892) teaches cytokine storm and cytokine release syndrome are life-threatening systemic inflammatory syndromes involving elevated levels of circulating cytokines and immune-cell hyperactivation that can be triggered by various therapies, pathogens, cancers, autoimmune conditions, and monogenic disorders (p. 2255, first paragraph, lines 9-13). Therefore, one of ordinary skill in the art would have recognized cytokine storm and cytokine release syndrome as diseases associated cytokine overproduction that may be caused by a triggered by a wide range of conditions.
Yi (Yi, Y.-S.; et al. Mediators of Inflammation 2014, Article ID 270302; cited in PTO-892) teaches that inflammation is the body’s first immune response to protect our body from harmful stimuli, such as pathogen infection, damaged cells, and irritants (p. 1, Introduction section, lines 1-3). In addition, Yi teaches that chronic inflammation is a leading cause of inflammatory/autoimmune diseases, such as rheumatoid arthritis (RA), Alzheimer’s diseases, systemic lupus erythematosus (SLE), asthma, psoriasis, atherosclerosis, and cancers (p. 1, right column, lines 3-6).
Yi further teaches that macrophages play a critical role in the inflammation that occurs during innate immune responses and are activated by the binding with various stimuli, including lipopolysaccharide (LPS), cytokines (e.g., interleukin-1, and tumor necrosis factor-α), and other chemical mediators through their receptors (e.g., toll-like receptors (TLRs) and dectin-1) (p. 1, last paragraph, line 6 to p. 2, line 4).
Calder (Calder, P. C.; et al. British Journal of Nutrition 2009, Vol. 101(S1), pp. 1-45; cited in PTO-892) teaches that inflammation is a stereotypical physiological response to infections and tissue injury; it initiates pathogen killing as well as tissue repair processes and helps to restore homeostasis at infected or damaged sites. Calder teaches that acute inflammatory reactions are usually self-limiting and resolve rapidly, due to the involvement of negative feedback mechanisms. Thus regulated inflammatory responses are essential to remain healthy and maintain homeostasis. However, inflammatory responses that fail to regulate themselves can become chronic and contribute to the perpetuation and progression of disease (p. S1, Abstract, lines 1-4).
Calder teaches that characteristics typical of chronic inflammatory responses underlying the pathophysiology of several disorders include loss of barrier function, responsiveness to a normally benign stimulus, infiltration of inflammatory cells into compartments where they are not normally found in such high numbers, and overproduction of oxidants, cytokines, chemokines, eicosanoids and matrix metalloproteinases. Calder teaches that the levels of these mediators amplify the inflammatory response, are destructive and contribute to the clinical symptoms (p. S1, Abstract, lines 5-8).
Calder further teaches an overview of different disease states of different organs, having different triggering factors, antigens involved, cells involved, mediators involved, different biomarkers, and different clinical features (p. 15, table 1).
Finally, Calder teaches that various dietary components including have the potential to modulate predisposition to chronic inflammatory conditions and may have a role in their therapy (p. S1, Abstract, lines 8-10). Calder teaches these components act through a variety of mechanisms including decreasing inflammatory mediator production through effects on cell signaling and gene expression, reducing the production of damaging oxidants, and promoting gut barrier function and anti-inflammatory responses, but in general, strong evidence of benefit to human health through anti-inflammatory actions is lacking for most of these dietary components (p. S1, Abstract, lines 10-14).
Galdiero (Galdiero, M. R.; et al. Cold Spring Harbor Perspectives in Biology 2018, 10:a028662; cited in PTO-892) teaches there is compelling evidence that cellular and humoral components of the tumor microenvironment have a large impact on cancer initiation and progression and on the resilience of most tumors in the face of therapy. Galdiero teaches that macrophages and neutrophils are both integrated within cancer-related inflammation and can take part in the various phases of tumor initiation and progression, and that cancer cells, tumor-associated macrophages, and neutrophils can release a plethora of protumorigenic and proangiogenic cytokines/chemokines p. 11, left column, Concluding Remarks, lines 11-14)
Therefore, one of ordinary skill in the art on the effective filing date of the present application would have recognized that the full scope of diseases associated with cytokine overproduction is extremely broad and would encompass inflammatory and autoimmune diseases, cancer, and excessive immune responses to pathogenic materials that manifest as cytokine storms.
In addition, one of ordinary skill in the art would have recognized that many of these diseases impact different organs, have different triggering factors, antigens involved, cells involved, mediators involved, different biomarkers, and different clinical features.
The prior art does not provide an expectation that administration of a composition comprising D-allose may reasonably treat the full scope of diseases associated with cytokine overproduction.
The relative skill of those in the art: The relative skill of those in the art is high.
The predictability or unpredictability of the art: The biological arts are unpredictable. For example, Fajgenbaum teaches cytokine storm and cytokine release syndrome can be triggered by many different factors, including various therapies, pathogens, cancers, autoimmune conditions, and monogenic disorders. Similarly, Calder teaches different inflammatory disease states vary by triggering factors, antigens involved, cells involved, mediators involved, and different biomarkers, suggesting that treatment of one inflammatory condition does not predict treatment of a different inflammatory condition. Therefore, the full scope of diseases associated with cytokine overproduction that may be treated by administering composition comprising D-allose to a subject is unpredictable.
The breadth of the claims: The scope of the claims is extremely broad and encompasses a method for treatment of any disease associated with cytokine overproduction in a subject.
The amount of direction or guidance presented: The specification provides that plasmacytoid dendritic cells can produce high amounts of type I interferon (p. 1, lines 18-22), and augments a biological defense during viral infection (p. 1, lines 24-25). The specification further provides that in autoimmune diseases such as systemic lupus erythematosus (SLE) or psoriasis vulgaris, complexes comprising patient-derived nucleic acids and proteins activate plasmacytoid dendritic cells, inducing high production of type I interferon, which elicits activation of immunocytes accelerating production of autoantibodies and is thought to further lead to reactivation of plasmacytoid dendritic cells (p. 1, lines 25-32). The specification suggests that this cycle of reactivation of plasmacytoid dendritic cells may be interrupted by production of type I interferon by plasmacytoid dendritic cells p. 1, lines 35-36).
The specification further provides that the disease associated with cytokine overproduction may be selected from the group consisting of collagen disease, joint or muscular inflammation or pain (such as chronic rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis or uric acid arthritis), skin inflammation (such as eczema), systemic lupus erythematosus, inflammatory chronic kidney conditions (such as glomerular nephritis, lupus nephritis or membranous nephritis), Sjogren's syndrome, and psoriasis (p. 3, lines 25-30).
The presence or absence of working examples: The specification provides working examples of treatment of conventional dendritic cells and plasmacytoid dendritic cells isolated from mice spleen cells with D-allose in cell culture. Specifically, these cells were treated with a TLR7 (polyuridylic acid) or TLR 9 ligand (CpG DNA) to stimulate cytokine production, and the levels of interferon-α (IFN- α) and interleukin-12 (IL-12) in the culture supernatant was measured (p. 14, lines 20-22). The specification provides that when D-allose was included in
the medium instead of D-glucose, cytokine production accompanying the stimulation was found
to be notably attenuated, but when D-allulose, L-allulose, D-glucose or D-fructose was used, attenuation of cytokine production was not observed (p. 14, lines 22-25; results in Figure 2).
The specification further provides that the cDC subset of dendritic cells produce IL-12 after CpG DNA stimulation, but that IL-12 production was not lowered even when D-allose was included in the medium (p. 14, lines 27-29; results in Figure 3). In addition, the specification provides that macrophages in the intraperitoneal region of mice produce TNF-α upon lipopolysaccharide (LPS) stimulation, simultaneously producing nitric oxide, and this response was not attenuated whether including D-allose, D-allulose, L-allulose or D-fructose in the medium (p. 14, lines 29-32).
The specification does not provide working examples showing the presently claimed compounds treating any diseases associated with cytokine overproduction.
Note that lack of working examples is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art such as treatment of the full scope of diseases associated with cytokine overproduction. See MPEP 2164.
The quantity of experimentation necessary: In order to practice the method of treatment of the full range of diseases associated with cytokine overproduction, one of ordinary skill in the art would be required to undertake a novel and extensive research program into the treatment all diseases associated with cytokine overproduction by administering a composition comprising D-allose or derivative thereof. Because this research would have to be exhaustive, and because it would involve such a wide and unpredictable scope of diseases associated with cytokine overproduction associated with different symptoms, having different causes, different triggering factors and involving different cell types, it would constitute an undue and unpredictable experimental burden.
Genentech, 108 F.3d 1361 at 1366, states that, “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion.” And “patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.”
Therefore, in view of the Wands factors, as discussed above, particularly the breadth of the claims and the nature of the invention, Applicants fail to provide information sufficient to practice the claimed invention of a method for treatment for the full scope of diseases associated with cytokine overproduction.
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 13 and 19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 13 depends from claim 11 and requires the cytokine is type I interferon. However, claim 11 recites a disease associated with cytokine overproduction and a cytokine production suppressing composition. It is unclear if claim 13 requires that the disease must be associated with type I interferon overproduction, the cytokine production suppressing composition must be a type I interferon suppressing composition, or both.
Claim 19 depends from claim 18 and requires the health functional food is a specified health food or nutritional functional food. However, the specification does not define a specified health food or nutritional functional food, and one of ordinary skill in the art would not reasonably recognize which specific health functional foods are considered as specified health foods or nutritional function foods and which specific health functional foods are not.
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.
Claim 14 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 14 depends from claim 11 and requires the D-allose is a D-allose and/or a derivative thereof, and/or a mixture of the same. However, as discussed in the above claim interpretation section, D-allose is defined by the specification to include D-allose and/or a derivative thereof and/or a mixture thereof. Therefore, claim 14 fails to further limit the subject matter of the claim upon which it depends.
For the purposes of promoting clarity in the claims, the examiner suggests amending claim 11 to replace the term “D-allose” with “D-allose and/or a derivative thereof, and/or a mixture of the same,” as defined in the specification.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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.
Claims 11 and 14-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Huang (Huang T.; et al. Brain Research 2016, vol. 1642, pp. 478-486; cited in IDS received December 8, 2023).
Claim 11 claims a method for treatment or prevention of a disease associated with cytokine overproduction in a subject, comprising: administering a cytokine production suppressing composition containing D-allose as the active ingredient, to the subject in need thereof.
Claim 12 depends from claim 11 and claims the method suppresses production of cytokines by plasmacytoid dendritic cells, claim 13 claims the cytokine is type I interferon, claim 14 claims the D-allose is D-allose and/or a derivative thereof, and/or a mixture of the same, and claim 15 further limits the D-allose derivative.
Claim 16 requires the composition is administered as a drug, claim 17 requires the composition is administered as a food, claim 18 requires the food is a health functional food or dietary supplement, and claim 19 requires the health functional food is a specified health food or nutritional function food.
Huang teaches the role of D-allose in the protection of blood-brain barrier (BBB) integrity and the relevant mechanisms involved in the mice model of middle cerebral artery occlusion and reperfusion (MCAO) (p. 478, Abstract, lines 3-4). Huang teaches that pretreatment of mice with D-allose ameliorated the neurological deficits, infarct volume, and brain edema in brains of MCAO/reperfusion mice. Huang further teaches that D-allose remarkably decreased BBB permeability, prevented the reduction of ZO-1, Occludin and Claudin-5 in mice brains with MCAO/Rep injury, and repressed the levels of TNF-α, NF-κB, interleukin (IL)-1β and IL-8 in inflammatory responses (p. 478, Abstract, lines 8-11) (emphasis added).
Huang concludes that D-allose may have therapeutic potential against brain ischemia reperfusion injury through attenuating BBB disruption and the inflammatory response via PPARγ-dependent regulation of NF-κB (p. 478, Abstract, lines 16-18).
Huang teaches that D-allose was intravenously injected via a tail vein (p. 478, Abstract, line 5). This is interpreted herein as the composition comprising D-allose being administered as a drug, as recited in claim 16.
Regarding the composition comprising D-allose as a cytokine production suppressing composition, because D-allose reduces the levels of, for example, TNF-α, it is reasonably considered as a cytokine production suppressing composition. Similarly, because Huang teaches that D-allose strongly reversed TNF-α and NF-κB activation in the mice of the MCAO/Rep (p. 482, right column, lines 1-2), ischemia/reperfusion associated with MCAO is reasonably considered as disease associated with cytokine overproduction.
Regarding the rejection of claim 15, claim 15 depends from claim 14 and further limits the D-allose derivative. Because claim 14 recites the D-allose derivative as an alternative to D-allose, the method of claim 14 can be practiced without the D-allose derivative. Accordingly, claim 15 further limits an alternative not required by claim 14, and thus Huang also anticipates claim 15.
Thus Huang anticipates claims 11 and 14-16.
Claims 11-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ueki 2007 (Ueki, M.; et al. Journal of Bioscience and Bioengineering 2007, vol. 104, pp. 304-308; cited in PTO-892) as evidenced by Deng (Deng, B.; et al. Cellular and Molecular Immunology 2020, vol. 18, pp. 219-229; cited in PTO-892).
Ueki 2007 teaches the inhibitory effect of D-allose on neutrophil activation after rat renal ischemia and reperfusion (p. 304, Title).
Ueki 2007 teaches that D-allose reduces the extent of rat renal ischemia/reperfusion (I/R) injury by suppressing the activation of neutrophils. Ueki 2007 teaches that the renal concentrations of cytokine-induced neutrophil chemoattractant (CINC)-1 and myeloperoxidase were significantly increased after renal ischemia/reperfusion. These increases were significantly inhibited by D-allose administration (p. 304, Abstract, lines 1-5). Ueki 2007 concludes by stating that their findings strongly suggest that D-allose protects against ischemia/reperfusion-induced renal injury by inhibiting the activation of neutrophils that play an important role in ischemia/reperfusion-induced renal injury (p. 304, Abstract, lines 7-9).
Ueki 2007 teaches that in the group of rats administered D-allose, animals were administered D-allose (400 mg/kg body weight) intravenously 30 min before ischemia/reperfusion (p. 305, left column, Experimental Protocol section, lines 6-7). Intravenous administration of D-allose is interpreted as the composition being administered as a drug, as recited in claim 16.
Regarding ischemia/reperfusion as a disease associated with cytokine overproduction, Ueki 2007 teaches there is a growing body of evidence that indicates that neutrophil infiltration into the kidney plays a crucial role in the induction of ischemia/reperfusion injury in rats
Ueki 2007 teaches the activation of neutrophils and the enhanced expression of adhesion
molecules on vascular endothelial cells facilitates the cascade processes of neutrophil infiltration,
which consist of rolling and adhesion onto vascular endothelial cells, and their transmigration across blood vessels. Ueki 2007 teaches that neutrophils infiltrating into the tissue release a various inflammatory cytokines and reactive oxygen species, leading to tissue injury (p. 304, left column, first paragraph, lines 3-14) (emphasis added). Therefore, ischemia/reperfusion is reasonably considered as a disease associated with cytokine overproduction.
Regarding the composition comprising D-allose as a cytokine production suppressing composition, because Ueki 2007 teaches D-allose suppressing the activation of neutrophils which release inflammatory cytokines, it is reasonably considered as a cytokine production suppressing composition.
Regarding claims 12 and 13, Ueki 2007 does not teach the method of claim 11, which suppresses production of cytokines by plasmacytoid dendritic cells and suppresses production of type I interferon. However, as evidenced by the present specification, contacting plasmacytoid dendritic cells with D-allose has the effect of suppressing type I interferon production from plasmacytoid dendritic cells upon stimulation with poly U or two types of CpG DNA (p. 14, lines 22-24).
MPEP 2112.01 (especially at I) citing In re Best, 562 F.2d 1252, 195 USPQ 430 (C.C.P.A. 1977) and In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) discusses the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions or characteristics that are newly recited or is identical to an invention instantly claimed. In such a situation the burden is shifted to the applicants to show the invention of the applicant and the prior art are not the same or that the prior art products do not necessarily possess the characteristics of the claimed invention.
The suppression of production of cytokines by plasmacytoid dendritic cells and of type I interferon is further evidenced by Deng, who teaches the role of pDCs in the pathogenesis of acute kidney injury (AKI) by using another model of AKI induced by ischemia reperfusion (IR). Deng teaches that IR-induced AKI resulted in an increased number of pDCs in the kidney at 24 h, and the intensity of expression of CD40, CD80, CD86, and MHC class II in pDCs was also elevated after IR (p. 224, left column, last paragraph, lines 1-7). Deng further teaches that pDC depletion alleviated renal dysfunction and histological lesions in IR-induced AKI (Fig. 6c and d). Moreover, pDC depletion by administration of diphtheria toxin (DT) resulted in significantly reduced infiltrating immune cells and cytokine expression in injured kidneys, suggesting a potent immune-stimulatory function of pDCs in IR-induced AKI, and that depletion of pDCs also resulted in reduced concentration of IFN-α (p. 224, left column, last paragraph, lines 7-15).
Therefore, both plasmacytoid DCs and Type I interferon would be expected to be present in a subject with renal ischemia/reperfusion, as evidenced by Deng, and would be effected by D-allose, as evidenced by the instant specification. Therefore claims 12 and 13 are also anticipated by Ueki 2007.
Regarding the rejection of claim 15, claim 15 depends from claim 14 and further limits the D-allose derivative. Because claim 14 recites the D-allose derivative as an alternative to D-allose, the method of claim 14 can be practiced without the D-allose derivative. Accordingly, claim 15 further limits an alternative not required by claim 14, and thus Ueki 2007 also anticipates claim 15.
Thus Ueki 2007 anticipates claims 11-16.
Claims 11 and 14-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ueki 2008 (Ueki, M.; et al. Journal of Bioscience and Bioengineering 2008, vol. 105, pp. 481-485; cited in PTO-892).
Ueki 2008 teaches that lipopolysaccharide (LPS) triggers sepsis syndrome by activating monocytes to produce proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, which potently stimulates the activation of neutrophils (p. 481, Abstract, lines 2-4).
Ueki 2008 teaches a study to examine the effects of D-allose on renal injury in the systemic inflammatory response induced by LPS administration, with emphasis on systemic TNF-alpha and the activation of neutrophils in the rat kidney. Ueki 2008 teaches that serum and renal TNF-alpha, renal cytokine-induced neutrophil chemoattractant (CINC)-1, and myeloperoxidase (MPO) concentrations, and renal function after LPS administration were evaluated, and that D-allose (400mg/kg body weight) inhibited LPS-induced increases in serum and renal TNF-alpha concentrations and in renal CINC-1 and MPO concentrations after LPS administration (p. 481, Abstract, lines 5-12).
Ueki 2008 teaches that male Wistar rats were injected intraperitoneally with LPS (20 mg/kg body weight) dissolved in 1 ml of sterile saline and divided into three experimental groups. (i) sham group in which animals were injected with the same volume of vehicle only without LPS; (ii) LPS-treated group in which rats were injected with LPS; and (iii) D-allose treated group, in which animals were injected intravenously with D-allose (400 mg/kg body weight) immediately after LPS administration (p. 481, right column, Materials and Methods section, second paragraph, lines 5-13). Ueki 2008 teaches that changes in serum TNF-alpha concentration 1 h after LPS administration were reduced by administration of 400 mg/kg D-allose (p. 482, Figure 1).
Ueki 2008 concludes by stating that D-allose may prove useful in protecting against acute renal injury in systemic inflammatory responses to LPS (p. 481, Abstract, lines 13-14).
In this instance, LPS-induced sepsis syndrome is a disease associated with cytokine overproduction, and because administration of D-allose reduces the serum levels of cytokines, the composition comprising D-allose administered by Ueki 2008 is a cytokine production suppressing composition.
In addition, intravenous administration of D-allose is interpreted as administration as a drug, as recited in claim 16.
Regarding the rejection of claim 15, claim 15 depends from claim 14 and further limits the D-allose derivative. Because claim 14 recites the D-allose derivative as an alternative to D-allose, the method of claim 14 can be practiced without the D-allose derivative. Accordingly, claim 15 further limits an alternative not required by claim 14, and thus Ueki 2008 also anticipates claim 15.
Thus Ueki 2008 anticipates claims 11 and 14-16.
Claims 11-15 and 17-19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yamamoto (Yamamoto, Y.; et al. Food Science and Technology Research 2017, vol. 23, pp. 319-327; cited in PTO-892), as evidenced by Møhlenberg (Møhlenberg, M.; et al. Cytokine 2019, vol. 124, 154519; cited in PTO-892) and Méndez-Sánchez (Méndez-Sánchez, N.; et al. Frontiers in Immunology 2021, vol. 12, article 641240; cited in PTO-892).
Yamamoto teaches that dietary D-allose ameliorates hepatic inflammation in mice with non-alcoholic steatohepatitis (NASH) (p. 319, title).
Yamamoto teaches that nonalcoholic steatohepatitis (NASH) is characterized by excess lipid accumulation and inflammation in hepatocytes. Yamamoto teaches that their study was designed to provide insight into the preventive effects of D-allose on the onset of NASH using mice treated with streptozotocin and fed a high-fat diet (HFD). Yamamoto teaches their experiments were initiated when the mice reached 5 weeks of age and lasted 3 weeks, and after the 3-week protocol, mice fed the HFD containing D-allose exhibited significantly decreased serum alanine aminotransferase levels, hepatic lipid accumulation and inflammation, and improved nonalcoholic fatty liver disease activity score compared to mice fed HFD without D-allose ( p < 0.05) (p. 319, Abstract, lines 1-7).
Yamamoto specifically teaches that mRNA expression levels of inflammation-related genes Mcp-1 (monocyte chemotactic protein-1, or Ccl2, chemokine (C-C motif) ligand 2) and Tnf-α (tumor necrosis factor alpha, or Tnf, tumor necrosis factor) were determined in the liver of control, the mice fed a high fat diet (STAM group), and the mice fed a high fat diet supplemented with D-allose (DA-STAM) using quantitative PCR (p. 323, left column, first full paragraph, lines 9-13), and that the relative mRNA levels of these transcripts (e.g., Tnf-α) were elevated in the STAM group compared with the control group, and reduced in the DA-STAM group compared with the STAM group (p. 325, Figure 4E and 4F).
Therefore, because Yamamoto teaches elevated levels of Tnf-α in NASH, it is reasonably considered as a disease associated with cytokine overproduction. In addition, because the food taught by Yamamoto comprising D-allose suppresses expression of Tnf-α, it is reasonably considered as a cytokine production suppressing composition.
Regarding claims 12 and 13, Yamamoto does not teach the method of claim 11, which suppresses production of cytokines by plasmacytoid dendritic cells and suppresses production of type I interferon. However, as evidenced by the present specification, contacting plasmacytoid dendritic cells with D-allose has the effect of suppressing type I interferon production from plasmacytoid dendritic cells upon stimulation with poly U or two types of CpG DNA (p. 14, lines 22-24). Therefore, absent a showing that oral administration of a food comprising D-allose, as disclosed by Yamamoto, does not inherently suppress cytokine production from plasmacytoid dendritic cells and does not inherently suppress type I interferon production, claims 12 and 13 are also anticipated by Yamamoto.
MPEP 2112.01 (especially at I) citing In re Best, 562 F.2d 1252, 195 USPQ 430 (C.C.P.A. 1977) and In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) discusses the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions or characteristics that are newly recited or is identical to an invention instantly claimed. In such a situation the burden is shifted to the applicants to show the invention of the applicant and the prior art are not the same or that the prior art products do not necessarily possess the characteristics of the claimed invention.
This rejection of claims 12 and 13 is further evidenced by Møhlenberg, who teaches that IFNαR1 knockout studies clearly demonstrate the involvement of type I IFN in the pathogenesis of NAFLD/NASH (p. 4, left column, first full paragraph, lines 15-19). In addition, Méndez-Sánchez teaches that plasmacytoid DCs respond to TLR7/8 ligands, mediate antiviral immunity by secreting type I interferons such as IFN-α (p. 4, left column, second paragraph, lines 8-12), and that in metabolic steatohepatitis, C57BL/6 mice fed with a methionine/choline-deficient (MCD)-diet there was a reduced expression of CD11c+ /MHCII+ /B220+ plasmacytoid DCs (pDCs) (p. 4, right column, lines 1-5). Méndez-Sánchez teaches that metabolic Associated Fatty liver disease (MAFLD) (previously non-alcoholic fatty liver disease) is a global health problem and represents the most common cause of chronic liver disease in the world. Méndez-Sánchez teaches that MAFLD spectrum goes from simple steatosis to cirrhosis, in between metabolic steatohepatitis with progressive fibrosis (p. 1, Abstract, lines 1-4). Metabolic steatohepatitis is interpreted as equivalent to nonalcoholic steatohepatitis taught by Yamamoto. Therefore, as evidenced by both Møhlenberg and Méndez-Sánchez, plasmacytoid DCs and Type I interferon would be expected to be present in a subject with metabolic steatohepatitis and, as evidenced by the instant specification, would be effected by administration of D-allose.
Regarding the rejection of claim 15, claim 15 depends from claim 14 and further limits the D-allose derivative. Because claim 14 recites the D-allose derivative as an alternative to D-allose, the method of claim 14 can be practiced without the D-allose derivative. Accordingly, claim 15 further limits an alternative not required by claim 14, and thus Yamamoto also anticipates claim 15.
Regarding claims 18-19, as described above, it is unclear how a specified health food or a nutrition functional food differ from health functional foods and foods in general. However, because Yamamoto includes D-allose in their food for the purposes of reducing hepatic inflammation in subjects with NASH, the food of Yamamoto is reasonably considered as a health functional food or nutrition functional food as recited in claims 18 and 19, absent evidence to the contrary, because it is intended to ameliorate the symptoms of NASH.
Thus Yamamoto anticipates claims 11-15 and 17-19.
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 11 and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Yamamoto (Yamamoto, Y.; et al. Food Science and Technology Research 2017, vol. 23, pp. 319-327; cited in PTO-892) in view of Izumori (U.S. pre-grant publication no. 20050245459 A1; cited in IDS received December 8, 2023).
The examiner asserts that Yamamoto anticipates claims 18-19, as described in the above rejection under 35 U.S.C. 102. However, for the sake of argument, if Yamamoto does not anticipate claims 18-19 because, for example, the food product comprising D-allose taught by Yamamoto does not qualify as a health functional food as recited in claim 18 or a specified health food or nutritional function food as recited in claim 19, then claims 11 and 17-19 would have been obvious over Yamamoto in view of Izumori.
Claim 11 claims a method for treatment or prevention of a disease associated with cytokine overproduction in a subject, comprising: administering a cytokine production suppressing composition containing D-allose as the active ingredient, to the subject in need thereof.
Claim 17 depends from claim 11 and requires the composition is administered as a food, claim 18 requires the food is a health functional food or dietary supplement, and claim 19 requires the health functional food is a specified health food or nutritional function food.
Yamamoto teaches as described in the above rejections under 35 U.S.C. 102.
Yamamoto does not teach their food product comprising D-allose as a health functional food as recited in claim 18, or as a specified health food or nutritional function food as recited in claim 19.
Izumori teaches their invention relates to a method of utilizing the physiological activity of rare saccharides, specifically D-allose and D-psicose, and to produce a functional food or drug utilizing the physiological activity of the rare saccharide (p. 1, [0012], lines 1-5) (emphasis added). Izumori further teaches the functional food of their invention is suitable for use in the fields of health foods for preventing particular diseases and of preventive medicines.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to formulate D-allose as a health functional food or a specified health food for ameliorating the effects of NASH. One of ordinary skill in the art would have been motivated to formulate D-allose as a as a health functional food or a specified health food for ameliorating the effects of NASH because Yamamoto teaches D-allose as reducing hepatic inflammation in subjects with NASH, and because Izumori teaches functional foods for use as health foods that comprise D-allose. Therefore, one of ordinary skill in the art would have recognized that D-allose, administered as a food by Yamamoto, may be specifically administered as a health functional food or specified health food for the purposes of treating NASH, as taught by Izumori.
Therefore the invention taken as a whole is prima facie obvious.
‘
As stated in the above rejection under 35 U.S.C. 112(b), it is unclear how a health
functional food differs from a specified health food or nutrition functional food. However, because Izumori teaches functional food comprising D-allose for use in the fields of health foods for preventing particular diseases and of preventive medicines, the examiner is interpreting this functional food taught by Izumori as satisfying the limitations of claims 18 and 19.
Conclusion
No claims are allowed.
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/B.M.B./Examiner, Art Unit 1693
/ANDREA OLSON/Primary Examiner, Art Unit 1693