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 .
Claims 1-20 are pending and are under examination.
Information Disclosure Statement
The information disclosure statement filed 7/25/23 has been considered and an initialed copy is enclosed.
Specification
The disclosure is objected to because of the following informalities:
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code wherever they may appear in the specification; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. See the following pages but not limited to page 16, 46 and 47, for example.
Appropriate correction is required.
Claim Objections
Claim 4 is objected to because of the following informalities: Claim 4 recites “The method according to claim 1, further comprises”. This should read “The method according to claim 1, further comprising”. Appropriate correction is required.
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 1, 3-11 and 13-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are drawn to a method of treating a tumor, comprising administering a probiotic to a subject in need, wherein the probiotic comprises Bifidobacterium animalis subsp. Lactis and a pharmaceutical composition comprising the probiotic for tumor treatment.
The claims recite that the probiotic comprises a bacterium with an evolutionary distance of less than 0.005 from the Bifidobacterium animalis subsp. Lactis NexStrain 02; preferably, the probiotic comprises a bacterium with an evolutionary distance of less than 0.001 from the Bifidobacterium animalis subsp. Lactis NexStrain 02; preferably, the probiotic comprises a bacterium with an evolutionary distance of less than 0.0005 from the Bifidobacterium animalis subsp. Lactis NexStrain 02; preferably, the probiotic comprises a bacterium with an evolutionary distance of less than 0.00005 from the Bifidobacterium animalis subsp. Lactis NexStrain 02; preferably, the probiotic comprises a bacterium with an evolutionary distance of 0 from the Bifidobacterium animalis subsp. Lactis NexStrain 02; maximal unique match (MUM) between two genomes is calculated from the evolutionary distance by using a suffix tree algorithm of parsnp software, MIUMi is calculated by using MUM, and a value of the MUMi is a distance between the two genomes; and a MUMi calculation method is: MUMi=1-Lmum/Lav, wherein the Lmum refers to a base number of all MUMs, and Lay refers to a mean of the base numbers of the two genomes.
The claims are drawn to treating a tumor including a digestive tract tumor or breast tumor, colorectal cancer or breast cancer.
The claims also recite that the method can improve a therapy response of a patient to the PD-1 inhibitor; the method can prolong patient's survival time, inhibit tumor growth, and/or improve enrichment of anti-tumor immune cells at a tumor site; and the anti-tumor immune cells are selected from one or more of CD4+CD62L-CD44+, CD8+IFN-gamma+, CD4+TNF- alpha+, CD1Ic+CD86+, and/or Gr-1+CD86+.
The claims are drawn to a genus of Bifidobacterium animalis subsp. Lactis strain that have the recited functions set forth in the claim i.e. to treat tumors etc.
There are many strains of Bifidobacterium animalis subsp. Lactis. For example, the specification calculates the evolutionary distance of 82 published strains of Bifidobacterium animalis subsp. The specification calculates the evolutionary distance from NexStrain 02 for the 82 strains and discloses the evolutionary distance in table 13.
The specification teaches that an average tumor volume of the mice model of colon cancer administered a NexStrain 02+ isotype control group (sterile normal saline) had no significant difference statistically compared with control group
However, an average tumor volume of the mice model of colon cancer administered NexStrain 02+ aPD-1 (anti-PD-1) group had a significant difference statistically compared with control group, with a p-value of 0.002 and a relative tumor growth inhibition rate TGI (%) of 42%.
The survived mice model of colon cancer survived longer when administered the NexStrain 02+ aPD-1 group treatment group as compared to control. See fig. 3.
In the breast cancer mice model, on day 21 after cell inoculation of all mice in all groups of the 4T1 model, it can be seen from the tumor growth of the mice in each group: on Day 21, an average tumor volume of the mice in control group is 963.36 mm³; an average tumor volume of the mice in NexStrain 02 alone treatment group is 854.46 mm₃, which has no significant difference statistically compared with control group; an average tumor volume of the mice in the aPD-1 alone treatment group is 756.32 mm³, which has no significant difference statistically compared with control group; and
an average tumor volume of the mice in NexStrain 02 and aPD-1 combination treatment group is 584.72 mm³, which has a significant difference statistically compared with control group, with a tumor growth inhibition rate of about 40% (FIG. 4).
For the breast cancer mice model, NexStrain 02 + aPD-1combination treatment group has significant differences compared with control group in the following indicators: CD4+CD62L-CD44+, CD8+IFN-gamma+, CD4+TNF-alpha+ and Cr-1+CD86+. In addition, NexStrain 02 + aPD-1 treatment group has significant difference compared with the sterile normal saline + aPD-1 group in the following indicators: CD8+IFN-gamma+, CD4+TNF-alpha+, CD11c+CD86+ and Cr-1+CD86+, indicating that NexStrain 02 can promote the enrichment of T cells and dendritic cells, and improve the response of PD-1 by stimulating the immune system to improve the response of PD-1, inhibit the tumor growth, improve the survival rate, and prolong the survival time.
In the digestive tract tumor mice model, an average tumor volume of the mice in NexStrain 02 alone treatment group 1 had no significant difference statistically compared with control group. However, an average tumor volume of the mice in NexStrain 02 combination treatment group had a significant difference statistically compared with control group.
In the digestive tract tumor mice model, the NexStrain 02 and aPD-1 combination treatment group can significantly prolong the survival time of the mice as compared with control group. See Table 12 and FIG. 10.
The NexStrain 02 (NexStrain 0-generation) was cultured for 50 and 100 passages to yield NexStrain 50-generation and NexStrain 100-generation. Using the NexStrain 02 (NexStrain 0-generation) as a reference sequence an evolutionary distance was calculated using the PARSNP software.
The specification teaches that the calculation method is: MUMi = 1-Lmum/Lav (Lₘum refers to a base number of all MUMs, and Lav refers to a mean of the base numbers of two genomes), and the MUMi value is the distance between the two genomes. The specification teaches that by calculating distances between NexStrain 50- generation, NexStrain 100-generation as well as the published 82 strains of Bifidobacterium animalis subspecies and NexStrain 0-generation, a distance between each NexStrain 0-generation, NexStrain 50-generation and NexStrain 100-generation is 0. A closest distance between the other published 82 strains of Bifidobacterium animalis subspecies and NexStrain 0 generation is 0.00003. See Table 13.
The specification does not disclose any member of the genus of Bifidobacterium animalis subspecies Lactis that can treat tumors, prolong a patients survival time, inhibit tumor growth and improve enrichment of anti-tumor immune cells at a tumor site when administered alone.
The specification teaches that reduction in tumor volume and increased survival time was seen with treatment with a combination of Bifidobacterium animalis subspecies Lactis and anti-PD1. Bifidobacterium animalis subspecies Lactis alone had no difference as compared to control in terms of tumor volume and survival in 3 different types of cancer models.
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, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., 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 applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
The specification discloses the NexStrain 02 which when administered alone does not have any effect on tumor volume or survival in three different types of cancer mice models.
Even though the specification discloses how to screen for B. animalis subsp. Lactis strains that have an evolutionary distance of less than 0.005 from NexStrain 02, the specification does not teach that any of these strains can treat tumors or improve survival from cancer when administered alone.
The written description provision of 35 U.S.C. § 112 are severable from its enablement provision Vas-Cath, Inc. v. Mahurkar, 1115 and possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69USPQ2d at 1895.
The disclosure of NexStrain 02 (isolated from human feces) is not representative of the genus of B. animalis subsp Lactis that can treat tumors, prolong a patients survival time, inhibit tumor growth and improve enrichment of anti-tumor immune cells at a tumor site when administered alone or with tumor therapeutic drugs.
The state of the art teaches that although commensals in the gut are often the source of probiotic strains, until these strains are isolated, characterized and a credible case presented for their health effects, they cannot be called 'probiotics'.
The effects of probiotics at the intestinal or extraintestinal level, including immune effects, are more likely to be strain-specific and claims of such benefit can only be made for strains or species in which the mechanistic basis has been demonstrated. Furthermore, robust evidence must be provided for benefits tied to specific strains. See Hill et al. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 11, 506–514 (2014).
Thus, the health effects of one strain cannot be extrapolated to other strains of the same species. In the instant case, the tested NexStrain 02 did not provide any health or immune effects regarding tumors or cancer when administered alone.
In view of these considerations, as of the effective filing date of the instant invention applicants were not in possession of the genus of Bifidobacterium animalis subsp Lactis strains including those that have an evolutionary distance of less than 0.005 from NexStrain 02 that can treat a tumor, prolong a patients survival time, inhibit tumor growth and improve enrichment of anti-tumor immune cells at a tumor site.
Claims 1-20 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 of treating a tumor comprising administering a combination of Bifidobacterium animalis subsp. Lactis NexStrain 02 and anti-PD1, does not reasonably provide enablement for a method of treating a tumor comprising administering Bifidobacterium animalis subsp. Lactis alone or administering Bifidobacterium animalis subsp. Lactis NexStrain 02 alone or administering any Bifidobacterium animalis subsp. Lactis strain including NexStrain 02 with any other tumor therapeutic drug.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the Invention
The claims are drawn to a method of treating a tumor, comprising administering a probiotic to a subject in need, wherein the probiotic comprises Bifidobacterium animalis subsp. Lactis and a pharmaceutical composition comprising the probiotic for tumor treatment.
The claims recite that the probiotic comprises a bacterium with an evolutionary distance of less than 0.005 from the Bifidobacterium animalis subsp. Lactis NexStrain 02; preferably, the probiotic comprises a bacterium with an evolutionary distance of less than 0.001 from the Bifidobacterium animalis subsp. Lactis NexStrain 02; preferably, the probiotic comprises a bacterium with an evolutionary distance of less than 0.0005 from the Bifidobacterium animalis subsp. Lactis NexStrain 02; preferably, the probiotic comprises a bacterium with an evolutionary distance of less than 0.00005 from the Bifidobacterium animalis subsp. Lactis NexStrain 02; preferably, the probiotic comprises a bacterium with an evolutionary distance of 0 from the Bifidobacterium animalis subsp. Lactis NexStrain 02; maximal unique match (MUM) between two genomes is calculated from the evolutionary distance by using a suffix tree algorithm of parsnp software, MIUMi is calculated by using MUM, and a value of the MUMi is a distance between the two genomes; and a MUMi calculation method is: MUMi=1-Lmum/Lav, wherein the Lmum refers to a base number of all MUMs, and Lav refers to a mean of the base numbers of the two genomes.
The claims recite treating a tumor including a digestive tract tumor or breast tumor, colorectal cancer or breast cancer.
The claims also recite that the method can improve a therapy response of a patient to the PD-1 inhibitor; the method can prolong patient's survival time, inhibit tumor growth, and/or improve enrichment of anti-tumor immune cells at a tumor site; and the anti-tumor immune cells are selected from one or more of CD4+CD62L-CD44+, CD8+IFN-gamma+, CD4+TNF- alpha+, CD1Ic+CD86+, and/or Gr-1+CD86+.
Breadth of the Claims
There are many strains of Bifidobacterium animalis subsp. Lactis. For example, the specification calculates the evolutionary distance of 82 published strains of Bifidobacterium animalis subsp. See table 13.
The breadth of tumors is also very large. They could be benign or malignant. When they are cancerous, they could be as a result of but not limited to cancers such as regulated by tumors or malignant cell populations, proliferation, or metastasis, including solid cancers and non-solid cancers. Examples of cancers include, but are not limited to, lung cancer, kidney cancer, gastric cancer, breast cancer, brain cancer, prostate cancer, hepatocellular cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urethral cancer, thyroid cancer, melanoma, head and neck cancers, colon cancer, leukemia, lymphoma, skin cancer, gastric cancer, esophageal cancer, myeloma, rectal cancer, bone cancer, uterine cancer, prostate cancer, and hematologic malignancies.
Guidance in the Specification/The Existence of Working Examples
The specification teaches that an average tumor volume of the mice model of colon cancer administered NexStrain 02+ isotype vs control group (sterile normal saline) had no significant difference statistically compared with control group
However, an average tumor volume of the mice model of colon cancer administered a combination of NexStrain 02+ aPD-1 group has a significant difference statistically compared with control group, with a p-value of 0.002 and a relative tumor growth inhibition rate TGI (%) of 42%.
The mice model of colon cancer survived longer with the NexStrain 02+ aPD-1 group treatment group as compared to control. See fig. 3.
In the breast cancer mice model, on day 21 after cell inoculation of all mice in all groups of the 4T1 model, it can be seen from the tumor growth of the mice in each group: on Day 21, an average tumor volume of the mice in control group is 963.36 mm³; an average tumor volume of the mice in NexStrain 02 alone treatment group is 854.46 mm₃, which has no significant difference statistically compared with control group; an average tumor volume of the mice in the aPD-1 alone treatment group is 756.32 mm³, which has no significant difference statistically compared with control group; and
an average tumor volume of the mice in NexStrain 02 combination treatment group is 584.72 mm³, which has a significant difference statistically compared with control group, with a tumor growth inhibition rate of about 40% (FIG. 4).
For the breast cancer mice model, NexStrain 02 + aPD-1 combination treatment group has significant differences compared with control group in the following indicators: CD4+CD62L-CD44+, CD8+IFN-gamma+, CD4+TNF-alpha+ and Cr-1+CD86+. In addition, NexStrain 02 + aPD-1 treatment group has significant difference compared with the sterile normal saline + aPD-1 group in the following indicators: CD8+IFN-gamma+, CD4+TNF-alpha+, CD11c+CD86+ and Cr-1+CD86+, indicating that NexStrain 02 can promote the enrichment of T cells and dendritic cells, and improve the response of PD-1 by stimulating the immune system to improve the response of PD-1, inhibit the tumor growth, improve the survival rate, and prolong the survival time.
In the digestive tract tumor mice model, an average tumor volume of the mice in NexStrain 02 alone treatment group 1 has no significant difference statistically compared with control group. However, an average tumor volume of the mice in NexStrain 02 combination treatment group has a significant difference statistically compared with control group.
In the digestive tract tumor mice model, the NexStrain 02 + aPD1 combination treatment group can significantly prolong the survival time of the mice as compared with control group. See Table 12 and FIG. 10.
The NexStrain 02 (NexStrain 0-generation) was cultured for 50 and 100 passages to yield NexStrain 50-generation and NexStrain 100-generation. Using the NexStrain 02 (NexStrain 0-generation) as a reference sequence an evolutionary distance was calculated using the PARSNP software.
The specification teaches that the calculation method is: MUMi = 1-Lmum/Lav (Lₘum refers to a base number of all MUMs, and Lav refers to a mean of the base numbers of two genomes), and the MUMi value is the distance between the two genomes. The specification teaches that by calculating distances between NexStrain 50- generation, NexStrain 100-generation as well as the published 82 strains of Bifidobacterium animalis subspecies and NexStrain 0-generation, a distance between each NexStrain 0-generation, NexStrain 50-generation and NexStrain 100-generation is 0. A closest distance between the other published 82 strains of Bifidobacterium animalis subspecies and NexStrain 0 generation is 0.00003. See Table 13.
The specification does not disclose any B. animalis subsp. Lactis that can treat tumors when administered alone.
State of the Art and Predictability of the Art and Amount of experimentation Necessary
The state of the art teaches that although commensals in the gut are often the source of probiotic strains, until these strains are isolated, characterized and a credible case presented for their health effects, they cannot be called 'probiotics'.
The effects of probiotics at the intestinal or extraintestinal level, including immune effects, are more likely to be strain-specific and claims of such benefit can only be made for strains or species in which the mechanistic basis has been demonstrated. Furthermore, robust evidence must be provided for benefits tied to specific strains. See Hill et al. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 11, 506–514 (2014).
The specification teaches that the NexStrain 02 alone or aPD1 alone did not treat tumors but the combination was able to decrease the volume of tumors, improve survival and induce certain immune cell types.
Thus, it is unpredictable that any B. animalis subsp. Lactis can treat tumors without further experimentation. Evidence of a health benefit is required for a probiotic. See Hill et al.
The specification does not provide any contrary evidence and they only B. animalis subsp. lactis strain tested or the therapeutic drug tested aPD1 did not have any effect in treating tumors in three different types of cancer model.
"The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art." "The "amount of guidance or direction" refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling". In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) and MPEP 2164.03.
More information is needed to have been stated in the specification in order to enable the full scope of using B. animalis subsp. Lactis alone to treat tumors as this probiotic effect cannot be predicted unless tested. It might be that B. animalis subsp Lactis strains cannot treat tumors if one of ordinary skill in the art extrapolated from the lack of efficacy when NexStrain 02 was administered alone.
For these reasons, other B. animalis subsp Lactis strains have to be tested for anti-tumor properties and it could be predicted that this could be undue experimentation since anti-tumor effects was seen only when the NexStrain 02 was combined with anti-PD1. It is not clear whether other chemotherapeutic drugs can be combined with B. animalis subsp Lactis including NexStrain 02 to achieve the anti-tumor result.
For these reasons, the specification is not enabling for the full scope of the claims.
Claims 2-3 and 12-13 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is a biological deposit rejection.
The specification lacks complete deposit information for the deposit of Bifidobacterium animalis subsp. Lactis NexStrain 02. Because it is not clear that the bacteria with the properties of Bifidobacterium animalis subsp. Lactis NexStrain 02 are known and publicly available or can be reproducibly isolated from nature without undue experimentation and because the claims requires Bifidobacterium animalis subsp. Lactis NexStrain 02, a suitable deposit for patent purposes is required. Exact replication of the plasmid is an unpredictable event.
Applicant's referral in the specification to the preservation of the bacteria in the General Microbiological Center of the China Microbiological Culture Collection Management Committee on July 27, 2020, with an Accession number of CGMCC No. 20455 is an insufficient assurance that all required deposits have been made and all the conditions of 37 CFR §1.801-1.809 have been met.
If the deposit has been made under the provisions of the Budapest Treaty, filing of an affidavit or declaration by applicant or assignees or a statement by an attorney of record who has authority and control over the conditions of deposit over his or her signature and registration number stating that the deposit has been accepted by an International Depository Authority under the provisions of the Budapest Treaty, that all restrictions upon public access to the deposit will be irrevocably removed upon the grant of a patent on this application and that the deposit will be replaced if viable samples cannot be dispensed by the depository is required. This requirement is necessary when deposits are made under the provisions of the Budapest Treaty as the Treaty leaves this specific matter to the discretion of each State. Amendment of the specification to recite the date of deposit and the complete name and full street address of the depository is required.
If the deposits have not been made under the provisions of the Budapest Treaty, then in order to certify that the deposits comply with the criteria set forth in 37 CFR §1.801-1.809, assurances regarding availability and permanency of deposits are required. Such assurance may be in the form of an affidavit or declaration by applicants or assignees or in the form of a statement by an attorney of record who has the authority and control over the conditions of deposit over his or her signature and registration number averring:
(a) during the pendency of this application, access to the deposits will be afforded to the Commissioner upon request;
(b) all restrictions upon the availability to the public of the deposited biological material will be irrevocably removed upon the granting of a patent on this application;
(c) the deposits will be maintained in a public depository for a period of at least thirty years from the date of deposit or for the enforceable life of the patent of or for a period of five years after the date of the most recent request for the furnishing of a sample of the deposited biological material, whichever is longest; and
(d) the deposits will be replaced if they should become nonviable or non-replicable.
In addition, a deposit of biological material that is capable of self-replication either directly or indirectly must be viable at the time of deposit and during the term of deposit. Viability may be tested by the depository. The test must conclude only that the deposited material is capable of reproduction. A viability statement for each deposit of a biological material not made under the Budapest Treaty must be filed in the application and must contain:
1) The name and address of the depository;
2) The name and address of the depositor;
3) The date of deposit;
4) The identity of the deposit and the accession number given by the depository;
5) The date of the viability test;
6) The procedures used to obtain a sample if the test is not done by the depository; and
7) A statement that the deposit is capable of reproduction.
As a possible means for completing the record, applicant may submit a copy of the contract with the depository for deposit and maintenance of each deposit.
Applicant's attention is directed to In re Lundack, 773 F.2d. 1216, 227 USPQ 90 (CAFC 1985) and 37 CFR §1.801-1.809 for further information concerning deposit practice.
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 3-10 and 13-20 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.
Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim. In the instant claims, the claims recite the term “preferably”. This renders the claims indefinite because it is not clear whether the claims are limited to the limitation(s) qualified by “preferably”. Please remove the term “preferably” wherever they may occur in the claims.
Claim 6, 7 and 16-17 lacks antecedent because of the recitation “the PD-1 inhibitor”. There is no prior mention of “the PD-1 inhibitor” in the base independent claim 1 and claim 11, respectively.
Claim 7 and 17 lacks antecedent because of the recitation “the immune signaling pathway regulators alone”. There is no prior mention of “the immune signaling pathway regulators alone” in the base independent claim 1 and claim 11, respectively.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 11-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
The claim(s) recite(s) a pharmaceutical composition for tumor treatment, comprising a probiotic and a pharmaceutically acceptable carrier, wherein the probiotic comprises Bifidobacterium animalis subsp. Lactis.
The claims recite that the pharmaceutical composition comprises Bifidobacterium animalis subsp. Lactis NexStrain 02 (Accession Number: CGMCC No. 20455).
The claims recite that the probiotic comprises a bacterium with an evolutionary distance of less than 0.005 from the Bifidobacterium animalis subsp. Lactis NexStrain 02; preferably, the probiotic comprises a bacterium with an evolutionary distance of less than 0.001 from the Bifidobacterium animalis subsp. Lactis NexStrain 02; preferably, the probiotic comprises a bacterium with an evolutionary distance of less than 0.0005 from the Bifidobacterium animalis subsp. Lactis NexStrain 02; preferably, the probiotic comprises a bacterium with an evolutionary distance of less than 0.00005 from the Bifidobacterium animalis subsp. Lactis NexStrain 02; preferably, the probiotic comprises a bacterium with an evolutionary distance of 0 from the Bifidobacterium animalis subsp. Lactis NexStrain 02; wherein the maximal unique match (MUM) between two genomes is calculated from the evolutionary distance by using a suffix tree algorithm of parsnp software, MUMi is calculated by using MUM, and a value of the MUMi is a distance between the two genomes; and a MUMi calculation method is:MUMi=1 -Lmum/Lav, wherein the Lmum refers to a base number of all MUMs, and Lav refers to a mean of the base numbers of the two genomes.
STEP 1: THE CLAIMS ARE DRAWN TO A COMPOSITION OF MATTER
STEP 2A PRONG ONE – THE CLAIM RECITES A JUDICIAL EXCEPTION -SEE MPEP 2106.4
Bifidobacterium animalis subsp. Lactis is a product of nature. The Bifidobacterium animalis subsp. Lactis NexStrain 02 is a product of nature as evidenced by the fact that the bacteria was isolated from human feces. Regarding the Bifidobacterium animalis subsp. Lactis of claim 13, this also reads on Bifidobacterium animalis subsp. Lactis NexStrain 02 and other naturally occurring Bifidobacterium animalis subsp. Lactis -see table 13.
Regarding the combination of the probiotic and a pharmaceutically acceptable carrier – this is a nature based composition as there are two products of nature mixed together. The pharmaceutically acceptable carrier encompasses products of nature such as water, milk, sucrose, glucose, natural gums etc. There is no evidence that combining the probiotic and the carrier results in a probiotic or natural carrier that is markedly different from the probiotic or carrier, respectively. There is also no evidence that the combination of the probiotic and carrier react together in any manner. Therefore, the combination of the probiotic and the pharmaceutically acceptable carrier is a nature-based product and the probiotic and carrier in the combination is compared to its respective natural counterpart. The probiotic and the broadly recited carrier are judicial exceptions.
The composition in an oral preparation or solution or suspension is still nature based as set forth above. The products in the oral preparation, solution or suspension could combine two judicial exceptions
and there is no evidence that natural carriers such as water, sucrose, glucose or milk and the probiotic react together and results in something "markedly different”. See Ass 'n for Molecular Pathology v. Myriad Genetics, Inc., 133 S.Ct. 2107, 2117 (2013).
The combination of natural products should be contrasted with cases like Chakrabarty where the Supreme Court found that, in contrast to the mixture of bacteria in Funk Brothers, “the patentee ha[d] produced a new bacterium (four plasmids were introduced into the bacterium) with markedly different characteristics from any found in nature and one having the potential for significant utility.” Diamond v. Chakrabarty, 447 U.S. 303, 310 (1980).
(“Natural phenomena, including naturally occurring organisms, are not patentable.”). See In re Roslin Institute (Edinburgh), 750 F.3d 1333, 1335-1336 (Fed. Cir. 2014). Supreme Court precedent teaches that neither isolating natural products nor combining them together represents an act of invention that would transform these naturally occurring products into patent eligible subject matter unless their combination results in something "markedly different”. See Ass 'n for Molecular Pathology v. Myriad Genetics, Inc., 133 S.Ct. 2107, 2117 (2013).
Regarding lyophilized powder, in Funk Brothers, “bacteria produced by the laboratory methods of culture [were] placed in a POWDER … base and packaged for sale to and use by agriculturists in the inoculation of the seeds of leguminous plants.” Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 129 (1948). Nevertheless, the Supreme Court concluded that such a mixture of bacteria was not patent eligible: “The qualities of these bacteria, like the heat of the sun, electricity, or the qualities of metals, are part of the storehouse of knowledge of all men. They are manifestations of laws of nature, free to all men and reserved exclusively to none.” Id. at 130. Thus, the Supreme Court did not find that routine production and extraction steps resulted in a product that was "markedly different" from the product of nature including the production of “powder” composition.
STEP 2A PRONG TWO – THE CLAIM DOES NOT RECITE ADDITIONAL ELEMENTS THAT INTEGRATE THE JUDICIAL EXCEPTION INTO A PRACTICAL APPLICATION. SEE MPEP 2106.4
Next, the claim as a whole is analyzed to determine whether any additional element or combination of elements that integrates the judicial exception into a practical application is recited.
The claims do not recite additional elements that integrate the judicial exception into a practical application such a particular treatment or prophylaxis for a disease or medical condition i.e. affirmatively reciting an action that effects a particular treatment or prophylaxis for a disease or medical condition. An example of said action is a step of administering the pharmaceutical composition comprising the probiotic to a subject and not merely an intended uses of the bacteria as recited in claims 11-20. See MPEP 2106.04(d)(2).
STEP 2B – THE CLAIMS DO NOT AMOUNT TO SIGNIFICANTLY MORE. SEE MPEP 2106.05.
Next, the claims a whole is analyzed to determine whether any additional element, or combinations of elements, is sufficient to ensure that the claim amounts to significantly more than the exceptions. Integration requires an additional element in the claim to apply, rely on, or use the judicial exception in a manner than imposes a meaningful limit on the judicial exception. The claims do not recite any meaningful additional limitations, modification(s) or transformation(s) that sufficiently ensures that the claim amounts to significantly more than the exceptions.
Thus, the claims as a whole does not amount to significantly more than the “product of nature” by itself. Thus, the claims does not qualify as eligible subject matter under 35 USC 101.
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.
Claim(s) 1, 4-11 and 14-20 is/are rejected under 35 U.S.C. 102(a)(a) as being anticipated by Sandy et al. CN 111356464 6-30-2020 cited in IDS.
Claim 1 and claim 11: Sandy et al discloses a method for treating a tumor, comprising administering a pharmaceutical composition comprising Bifidobacterium animalis subsp. Lactis (ATCC Deposit Number PTA-125097) and a pharmaceutically acceptable carrier.
Claim 4 and claim 14: Sandy et al disclose that the method further comprises an application of one or more other tumor therapeutic drugs such as immune checkpoint inhibitors for proteins CTLA4, PD-1, PD-L1, PD-L2, BTLA, KIR, LAG3, TIM-3.
Claim 5 and claim 15: Sandy et al disclose that the cancer is breast cancer or colorectal cancer (see description, paragraph 918).
Claim 6-7 and claims 16-17: Sandy et al disclose the method is for tumor immunotherapy. Sandy et al disclose the method further comprises administering cancer immunotherapy such as anti-PD-1 (PD-1 inhibitor) and thus the method can also improve a therapy response of a patient to the anti-PD-1; the method can prolong a patient’s survival time, inhibit tumor growth, and/or improve enrichment of anti-tumor immune cells at a tumor site wherein the anti-tumor cells are selected from one or more of CD4+CD62L-CD44+, CD8+IFN-gamma+, CD4+TNF-alpha+, CD11c+CD86+, and/or Gr-1+CD86+ and the pharmaceutical composition can improve enrichment of anti-tumor cells CD8+IFN-gamma+, CD4+TNF-alpha+, CD11c+CD86+, and/or Gr-1+CD86+ at the tumor site compared with treatment with the immune signaling pathway regulators alone.
Claim 8 and claim 18: Sandy et al disclose a single dosage of the probiotic is at least 109 CFU to at least 1013 CFU.
Claim 9 and claim 19: Sandy et al disclose that the pharmaceutical composition is an oral preparation such as freeze-dried (lyophilized) powder, capsules and liquids.
Claim 10 and claim 20: Sandy et al disclose the probiotic and the cancer therapeutic are administered simultaneously or nearly simultaneously (not used at the same time) e.g. administration occurs in one hour.
See entire translation of Sandy et al.
Status of Claims
Claims 1-20 are rejected.
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/OLUWATOSIN A OGUNBIYI/Primary Examiner, Art Unit 1645