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 .
Claim status
The amended claim set filed 01/18/2024 is acknowledged. Claims 2, 6-7, 13-20, 22 and 24-25 are pending and have been amended without introducing new matter. Claims 1, 3-5, 8-12, 21, 23 and 26-35 are cancelled. Claims 2, 6-7, 13-20, 22 and 24-25 are being considered on the merits.
Priority
The present application claims status as a 371 (National Stage) of PCT/CA2022/050437 filed on 03/23/2022. Applicant’s claim for benefit under 35 U.S.C. 119 (e) of Provisional application No. 63/165,539 filed on 03/24/2021 is acknowledged. The present application and all claims are being examined with the earliest effective filing date of 03/24/2021.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 12/12/2024 and 05/20/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Drawings
The drawings are objected to because:
-In Figures 1-8, the dots representing “no surgery” versus “surgery” are difficult to distinguish due to similar shading. In addition, the legend depicts a large dot followed by a small dot for each group which causes confusion, because it is not clear which dot is associated with each group or what the meaning is of the second dot.
-In Figure 7, the label for the y-axis is illegible because the character following “IFN” appears smudged.
-In Figure 8, the symbols used in the data plot (dots, triangles, asterisk) are not defined in the figure or in the brief description of drawings.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 13 is objected to because of the following informalities: the claim recites the list “MHCII, CD96, CD69, IFNγ” in line 4 without reciting a terminal conjunction before the last element of the list. Please correct to “MHCII, CD96, CD69, and IFNγ.” Appropriate correction is required.
Claim 14 is objected to because of the following informalities: the claim recites “FNγ” in line 7, which is clearly a misspelling of “IFNγ”. Appropriate correction is required.
Claim 17 is objected to because of the following informalities: the claim recites the list of biomarkers in the past tense (e.g., “upregulated… increased… downregulated) but also recites some members of this list in the present tense (e.g., “upregulate… downregulate”) in lines 9 and 11. For consistency, please choose the appropriate verb tense when amending the claim. Appropriate correction is required.
Claim 17 is objected to because of the following informalities: the claim recites “upregulate IL-7;j upregulate IL-12(p70); upregulated IL-13;j” in line 9, wherein the “j” is clearly a typographical error. Appropriate correction is required.
Claim Interpretation
Claim 19 recites a method comprising monitoring an immune response in a patient by monitoring for an immune activation biomarker, which may include (1) “MICA/B and related ligands expressed on human cells”, (2) “epigenetic changes associated with trained innate immunity”, and/or (3) “metabolic changes (glycolysis > oxidative phosphorylation) of immune cells”.
(1) Regarding the limitation of “MICA/B and related ligands expressed on human cells”, the prior art teaches that humans have two main types of ligands that bind to NKG2D, a family of class-I chain-related proteins A and B (MICA and MICB) and a family of six cytomegaloviral unique long 16 (UL16)-binding proteins (ULBP 1-6), whereas other species, for example, mice, may have additional NKG2D ligands (see, e.g., Liu et al. at pg. 2066, col. 2, para. 2; cited on Form 892). Hence, as the limitation requires that the ligands are “expressed on human cells”, the limitation is interpreted as including MICA, MICB, ULBP-1, ULBP-2, ULBP-3, ULBP-4, ULBP-5 and ULBP-6, while excluding all other NKG2D ligands.
(2) Regarding the limitation of “epigenetic changes associated with trained innate immunity”, rejections under 112(b) (indefiniteness) and 112(a) (written description) were each contemplated but have not been made for the following reasons.
The rationale for indefiniteness was based on a plain reading of the claims, wherein the monitoring of “epigenetic changes associated with trained innate immunity” includes said monitoring before any such “training” has occurred (i.e., prior to the administration step). However, a person of ordinary skill would have recognized that when monitoring for such “changes”, it may be desirable to obtain a baseline result prior to the administration. Furthermore, the prior art of Gunn et al. (US 20190134172 A1; cited on Form 892) discloses methods of treating cancer in a target tissue, comprising administering an immunogenic composition to a patient, wherein the composition modulates an innate immune response in the target tissue (see pg. 1, para. [0007]; pg. 2, para. [0010]) and further discloses that patients may advantageously be “screened” for disorders of innate immunity by analysis of epigenetic changes prior to the treatment (see pg. 25, para. [0230]). Hence, the scope of this limitation is broadly interpreted to include monitoring before the administration step.
In view of Netea et al. (cited on Form 892), the term “trained innate immunity” refers to an established biological process for innate immune memory (see Abstract). Netea et al. also discuss the innate stimuli and the epigenetic and metabolic reprogramming events that shape the induction of trained immunity (see Abstract). As particularly relevant to the present application, Gunn et al. provide substantial guidance regarding epigenetic changes associated with innate immunity, their associated biomarkers, and also relate these biomarkers to identifying immunodeficiencies and responsiveness to immunotherapy in a patient (see pgs. 25-26, paras. [0230]-[0233]). Hence, a person of ordinary skill would have been able to envisage the claimed genus of “epigenetic changes associated with trained innate immunity” in view of the prior art of record.
(3) Regarding the limitation of “metabolic changes (glycolysis > oxidative phosphorylation) of immune cells”, a rejection under 112(a) (written description) was contemplated but has not been made for the following reasons. The prior art of Sun et al. (cited on Form 892) provides a biochemical and molecular model to characterize metabolic reprogramming and their functional implication in anti-inflammatory, immune resolution, and proinflammatory responses (see Abstract). Sun et al. provides a table of metabolic changes associated with different immune cell types, and further, the stimuli, functional changes, and signal molecules involved in these immune responses (see “Table” on pg. 1993). Examiner notes that these metabolic changes include “↑Glycolysis, ↓OXPHOS”. Hence, a person of ordinary skill would have been able to envisage the claimed genus of “metabolic changes of immune cells” in view of the prior art of record.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2, 6-7, 13-20, 22 and 24-25 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 2 recites a method, wherein “the cancer forms a tumor in a target tissue, and/or the cancer is characterized by a potential to metastasize to the target tissue, wherein the subject undergoes surgical removal of the tumor on a surgery date”. This phrase renders the claim indefinite because it leads to multiple interpretations.
First, it may be interpreted that the entire phrase, “the cancer is characterized by a potential to metastasize to the target tissue, wherein the subject undergoes surgical removal of the tumor on a surgery date” is all the same limitation. If this were the case, the first limitation of “the cancer forms a tumor in a target tissue” does not require the surgical removal of the tumor on a surgery date. This interpretation further renders the claim indefinite because the administration step (lines 6-8) requires “the surgery date”.
Second, it may be interpreted that the phrases, “the cancer is characterized by a potential to metastasize to the target tissue” and “wherein the subject undergoes surgical removal of the tumor on a surgery date” are separate limitations. If this were the case, the surgical removal of the tumor on a surgery date is required in all embodiments.
However, because the first limitation (“the cancer forms a tumor in a target tissue”) is optional, either interpretation further renders the claim indefinite, because the tumor is required to be removed from the target tissue even when it has not yet metastasized to the target tissue. Here, the term “the tumor” recited in line 4 also lacks antecedent basis, because it refers to “a tumor [formed] in a target tissue” which is not required when selecting the second limitation.
Furthermore, the embodiment of the invention that combines both limitations (“wherein the cancer forms a tumor in a target tissue” and “the cancer is characterized by a potential to metastasize to the target tissue”) also renders the claim indefinite, because the cancer cannot have the “potential to metastasize” to the target tissue if the cancer (tumor) is already present in the target tissue.
Examiner notes the recited administration step of claim 2 requires a surgery date (lines 7-8) and that dependent claim 6 recites the further limitation, “wherein the tumor is removed from the target tissue”. Hence, in order to satisfy the requirements of 112(d), claim 2 must include embodiments wherein the tumor is not removed from the “target tissue”. However, the limitations of claim 2 still require the surgical removal of a tumor on a surgery date. Thus, in the interest of compact prosecution, the above limitations are interpreted as follows: (1) wherein the cancer forms a tumor in a target tissue and the subject undergoes surgical removal of the tumor from the target tissue on a surgery date or (2) the cancer is characterized by a potential to metastasize, wherein the subject undergoes surgical removal of any tumor from any tissue on a surgery date.
Claims 6 and 19 recite the limitation "The method of claim 1…" in line 1. There is insufficient antecedent basis for this limitation in the claim, because “claim 1” has been cancelled. In the interest of compact prosecution, the claims are reasonably interpreted as being directed to “The method of claim 2”.
Claims 7, 13-15, 17, 20, 24, recite the limitation "The method according to claim 1…" in line 1. There is insufficient antecedent basis for this limitation in the claim, because “claim 1” has been cancelled. In the interest of compact prosecution, the claims are reasonably interpreted as referring to “The method according to claim 2”.
Claim 14 also recites the limitation, “wherein the composition is administered in an amount effective in the perioperative period to modulate a biomarker that is: increased CD69 expression; reduced expression of CD96…”, etc. This renders the claim indefinite, because the plain meaning of the limitation is that the recited effects (e.g., “increased CD69 expression”) are the biomarkers to be modulated. As modulation includes affecting any change (e.g., increasing as well as decreasing), “to modulate… increased…expression” would include not only increasing said expression, but also decreasing said expression. On the other hand, it may also be interpreted that the recited effects (e.g., “increased CD69 expression”) specify how the biomarkers (e.g., “CD69”) have been modulated (e.g., “increased… expression”).
The examiner suggests that if the second interpretation above is what is intended by Applicant, the claim may be rendered definite by removing “modulate a biomarker” in line 3 and changing the recitations of “increased” and “decreased” to the present tense. For example, the claim may recite, “…in an amount effective in the perioperative period to: increase CD69 expression; reduce expression of CD96; increase expression of MHCII…”, etc.
Claim 17 recites the limitation “wherein the composition is administered in an amount effective in the perioperative period to modulate a biomarker that is: upregulated cytotoxic granules (perforin, granzymes A & B); upregulated NKG2D…”, etc. This renders the claim indefinite, because the plain meaning of the limitation is that the recited effect (e.g., “upregulated cytotoxic granules”) is the biomarker to be modulated. Hence, claim 17 is indefinite for at least the same reasons discussed regarding claim 14. In addition, claim 17 recites the following limitations that include parenthetical statements:
(A) “upregulated cytotoxic granules (perforin, granzymes A & B)”
(B) “upregulated chemokines CXCL9 & CXCL10 (IP-10)”
(C) “increased iNOS expression (as indicative of M1 macrophage polarization)”
(D) “upregulated CD86 (human M1 monocytes)”
(E) “upregulate IL-12(p70)”
(F) “downregulate CD163 (human M2 monocytes)”
First, it is unclear whether the phrases in parentheses provide (1) a synonym of the previously recited claim element, (2) an example of the previously recited claim element, or (3) a further limitation. For example, the “IP-10” of limitation B may be a synonym for “CXCL10”. However, the phrase “cytotoxic granules” in limitation A appears to be broader than “perforin” and “granzymes A & B”, which may be interpreted to either be examples or further limitations of “cytotoxic granules”. This then raises the question as to whether “IP-10” is merely a synonym of CXCL10 or a further example/species of “CXCL9 & CXCL10”. In this instance, both interpretations may be correct (i.e., IP-10 is a synonym of CXCL10 and is also a species of the recited genus), which leads to further confusion regarding the use of parentheses. Limitation C above recites “as indicative of…” in parentheses, which suggests a functional relationship, as opposed to a synonym or species. However, as the other terms in parentheses do not recite “as indicative of”, it is unclear how, for example, “upregulated CD86” relates to “human M1 monocytes” in limitation D. Furthermore, limitations D and F recite “human M1/M2 monocytes”. This raises the question as to whether the “CD86” or “CD163” are required to be human, in which case, it also raises the question as to whether the mammalian subject of the claim must also be human. Thus, the phrases in parentheses can be interpreted to have various meanings which renders all of the above limitations indefinite.
Furthermore, the elements recited in parentheses may be interpreted as reciting a narrower limitation of the previously recited claim element, which also renders the claim indefinite. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. In the instant case, it is unclear if the limitations recited in parentheses are required features of the claim. Applicant is reminded that the description of examples and preferences is properly set forth in the specification rather than in a single claim. A narrower range or preferred embodiment may also be set forth in another independent claim or in a dependent claim.
Claim 17 also recites “downregulated PD-1; and/or downregulated PDL1; downregulate CD163 (human M2 monocytes)” which renders the claim indefinite. It is unclear why the transitional phrase “and/or” is used before the second to last limitation of the claim but none is used before the final limitation of the claim. Thus, it is unclear if the phrase requires that the last two limitations must be selected together or if each are independent of each other. Applicant is reminded that when listing a set of alternatives, it is proper to use a single terminal conjunction (“and”, “or”, or “and/or”) only before the last item of the list in order to avoid confusion.
Claims 18-19 recite the limitation "the patient" in line 2 of each claim. There is insufficient antecedent basis for this limitation in the claim, because the parent claim(s) do not recite “a patient”.
Claim 19 recites multiple limitations which are followed by a parenthetical statement, wherein it is unclear if some of the terms/phrases recited in parentheses are intended to be synonyms, examples, or further limitations of the claims. For example:
(A) “KIR (Killer Inhibitory Receptors)”
(B) “myeloid suppressive cells (MDSCs)”
(C) “Treg cells (IL-10)”
(D) “soluble (cleaved) MICA/B”
(E) “metabolic changes (glycolysis > oxidative phosphorylation) of immune cells”
In the case of A and B above, the terms in parentheses appear to be an alternative phrasing of the preceding term (i.e., abbreviated versus unabbreviated forms) which do not by themselves render the claim indefinite. However, it is not apparent that limitations C-E use parentheses to convey the same meaning, rendering the scope of these limitations unclear.
For example, “Treg cells” and “IL-10” are clearly not synonyms, because interleukins are not cells. However, this also raises questions as to how the terms relate to one another. For example, it could be interpreted that “IL-10” narrows the type of Treg cell used as a biomarker (e.g., only those that express IL-10), or it could also be interpreted that this requires the monitoring of IL-10 instead of the Treg cell itself. In either case, it is unclear if “IL-10” is actually required or if it is merely an example. Similarly, in the case of limitation D, it is unclear whether “cleaved” is required for solubility (i.e., wherein “cleaved” is unequivocal to being “soluble”) or is merely an example of how to achieve solubility (i.e., an exemplification). Furthermore, whether or not this term relates to the MICA/B being “soluble” or not, it is still unclear whether it is a further limitation, because if it were required, it would not need to be recited in parentheses. Finally, while it is understood that “glycolysis > oxidative phosphorylation” is a “metabolic change”, it is unclear whether this is intended to be an example or further limitation of a “metabolic change”.
Where the limitations comprise both broader and narrower limitations, it is unclear if such narrower language is (a) merely exemplary, and therefore not required, or (b) a required feature of the claims. For example, if “glycolysis > oxidative phosphorylation” is considered to be a type of metabolic change, it is unclear if this specific type of metabolic change is required by the claim or is merely provided as an example. This applies to all of limitations C-E above. Applicant is reminded that the description of examples and preferences is properly set forth in the specification rather than in a single claim. A narrower range or preferred embodiment may also be set forth in another independent claim or in a dependent claim. See MPEP § 2173.05(c).
Claim 24 recites the limitations, wherein “the dosage duration is at least two weeks, optionally at least one week”, wherein the second recited limitation improperly broadens the scope of the first recited limitation. Here, the first limitation (“at least two weeks”) falls within the scope of the second limitation (“at least one week”), i.e., “two weeks” is already “at least one week”. Furthermore, the broader limitation is recited as being “optional” which renders the scope further unclear, because the limitation of “at least two weeks” cannot be both required and optional at the same time. Applicant is reminded that a broad limitation together with a narrow limitation that falls within the broad limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. A narrower limitation or preferred embodiment may also be set forth in another independent claim or in a dependent claim. See MPEP 2173.05(c).
Claim 25 recites the phrase, “wherein the doses are administered subcutaneously every day, or every other day, before and after the surgery date” (Emphasis added) which renders the claim indefinite, because this leads to multiple interpretations. Here, the claim comprises the form of “A or B before and after C”, where the recitation of multiple transition words within the claim leads to confusion over the intended scope. For example:
First, it may be interpreted that the doses are administered (A) every day (at any time relative to the surgery) or (B) every other day, before and after (C) the surgery date.
Second, it may be interpreted that the doses are administered (A) every day before and after (C) the surgery date or (B) every other day, before and after (C) the surgery date.
Third, it may be interpreted that the doses are administered (A) every day (at any time relative to the surgery) or (B) every other day before (C1) the surgery date and at any interval after (C2) the surgery date.
Fourth, it may be interpreted that the doses are administered (A) every day before (C1) the surgery date and at any interval after (C2) the surgery date or (B) every other day before (C1) the surgery date and at any interval after (C2) the surgery date.
Hence, the metes and bounds have not been clearly set forth.
Claims 16 is rejected for depending from an indefinite claim and for failing to rectify the indefiniteness of the claim from which it depend.
Claim Rejections - 35 USC § 103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 2, 6-7, 13-20, 22 and 24-25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gunn et al. (US 20190134172 A1; cited on Form 892), hereafter “Gunn”, and further in view of Matzner et al. (cited in the IDS filed on 12/12/2024 at Cite No. 17), hereafter, “Matzner”.
Regarding claim 2, Gunn teaches the use of an immunogenic composition in methods of treating an immune dysregulation in a target tissue of a mammalian host suffering from a disease or condition characterized by the immune dysregulation of the target tissue, such as a cancer (see pg. 1, para. [0007]; pg. 2, para. [0010]). Gunn teaches a preparation of a killed or attenuated microbes of one or more pathogenic microbial species, wherein the pathogenic microbial species is pathogenic in the corresponding specific organ or tissue in a healthy subject (see claim 38). Gunn teaches the use of the preparation, wherein the subject’s cancer is situated in the target tissue of skin, bone, brain or breast and the pathogenic microbial species is Staphylococcus aureus (see claims 8 and 39). Gunn teaches that the pathogenic bacterial species are administered to an individual in an amount effective to stop or slow progression or metastasis of the cancer, or to increase survival of the subject (see pg. 16, col. 2, para. [0207]). Gunn teaches that the microbial pathogens have a mammalian pattern recognition receptor (PRR) signature that is specific to the target tissue wherein the microbe is pathogenic (see pg. 1, col. 2, para. [0006]).
Gunn teaches that components of the microbial pathogens are associated with a repertoire of pattern recognition receptor (PRR) agonists which correspond to the PRRs of the innate immune system (see pg. 1, col. 2, para. [0006]; pgs. 1-2, para. [0008]), and treatment using such PRR ligands may be combined with more traditional and existing therapies for cancer, including surgery (see pg. 16, para. [0205]). Gunn also teaches that, as Example 22 illustrates, the site specific immunotherapy may be applied to the site of a surgical excision of a skin melanoma (see pg. 41, para. [0376]). Hence, Gunn suggests the treatment may include surgical removal of a tumor that has formed in a target tissue.
Gunn does not teach that the administration of the immunogenic composition is during a perioperative period that is within one month of the surgery date that the tumor is removed.
Matzner teaches that immunosuppression throughout the perioperative period is an established phenomenon that has been shown to accelerate metastatic progression in animal models (see pg. 314, col. 2, para. 2). Matzner teaches that although surgery is usually successful in completely removing the primary tumor, most patients continue to harbor minimal residual disease (MRD) in the form of dormant or active micro-metastases, and the biological stress responses to surgery have been shown to increase the risk of cancer recurrence (see pg. 313, col. 3, para. 2). Typically, anti-metastatic interventions, such as immunotherapy, are administered up to 1 month before surgery, and the immediate perioperative period (IPP), spanning a few days before and after surgery (including the surgical period itself), is rarely exploited for such interventions given the speculated concerns over contraindications to surgery (see pg. 313, cols. 1-2). Matzner’s disclosure challenges the necessity of this dissociation and advocates for greater recognition of the clinical potential of perioperative anti-metastatic interventions, especially immunotherapies (see pg. 313, col. 2). Matzner teaches that a solid biological rationale supports the likely efficacy of various potentially synergistic anti-metastatic interventions during the IPP, including approaches to enhance immune preservation, immunometabolism and anticancer immune responses, whilst limiting stress-inflammatory responses that might directly affect malignant tissue and promote disease progression (see pg. 313, col. 3, para. 1).
Examiner notes that Matzner also teaches that anti-metastatic perioperative therapies includes those that have a direct immunological mechanism of action, such as IL-2 or TLR9 agonists (see Matzner at pg. 320, cols. 1-2) which are included in the list of PRR agonists associated with pathogenic microbes disclosed by Gunn (see Gunn at pg 2, para. [0008]).
It would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention by combining the teachings of Gunn and Matzner, because both references relate to immunostimulatory therapies to treat cancer. Furthermore, Matzner teaches that such therapies, while typically administered up to a month before surgical removal of a tumor to avoid complications, may actually be more efficacious when administered closer to the surgery date. Hence, one would have immediately recognized the benefits of administering the immunogenic composition taught by Gunn during a period that is within less than a month, even within a few days, of the surgery date. Further, Matzner teaches such anti-metastatic interventions during the immediate perioperative period in combination with the surgical removal of a primary tumor to have a synergistic effect on treating cancer. Hence, one would have been particularly motivated to apply the combination in order to increase the efficacy of the cancer treatments and to reduce the risk of cancer recurrence. One would have also have had a reasonable expectation of success, because both approaches to treat cancer (i.e., immunogenic therapies, surgery) are commonly known in the art and both are taught by Matzner to work synergistically when used in combination. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Regarding claim 6, Gunn teaches administering an immunogenic composition to treat immune dysregulation in a target tissue, while Matzner teaches the surgical removal of a primary tumor from a subject undergoing an immunotherapy, as discussed above. Hence, the claim is obvious for the same reasons as claim 2.
Regarding claim 7, Gunn teaches the subject may be a human (see pg. 2, para. [0010]).
Regarding claim 13, Gunn teaches the composition may be adapted for use in an amount effective to modulate a biomarker (see pg. 2, para. [0011]). Example 29 of Gunn’s disclosure illustrates that site specific immunotherapies (administration of whole killed cells of a pathogenic bacteria) potentiate an immune response when used in combination with cancer antigens (see pg. 44, para. [0402]; pg. 27, para. [0269]). The results of this study showed that the site specific immunotherapy treatment, with or without the antigen, enhanced circulating levels of IFN-γ (see pg. 44, para. [0406]). Hence, it would have been obvious to have selected IFN-γ as the biomarker.
Regarding claim 14, Gunn teaches the composition may be adapted for use in an amount effective to modulate a biomarker, for example, neutrophils (see pg. 2, para. [0011]). Gunn teaches that the immunogenic composition may activate or expand neutrophils of the immune system (see pg. 17, para. [0213]) and elevated neutrophils in the blood of treated mice was demonstrated in several Examples of the disclosure (see, e.g., pg. 5, para. [0082] and FIG. 66). Hence, it would have been obvious to have administered the composition in an amount effective to increase neutrophil cell counts.
Regarding claim 15, Gunn teaches the composition may be used in an amount effective to modulate a biomarker selected from the group consisting of PD1, PDL1, IP-10, MIG, RANTES, neutrophils, Ly6C monocytes, and NKG2D (see claim 14). Hence, it would have been obvious to have administered the composition in an amount effective to modulate any of these biomarkers.
Regarding claim 16, Gunn teaches the composition is for use in an amount effective to down-regulate PD1 and/or PDL1 expression in cells present in the target tissue (see claim 15). Hence, it would have been obvious to have administered the composition in an amount effective to down-regulate PD1 and/or PDL1 expression in cells present in the target tissue.
Regarding claim 17, Gunn teaches the composition is for use in an amount effective to down-regulate PD1 and/or PDL1 expression in cells present in the target tissue (see claim 15). Hence, it would have been obvious to have administered the composition in an amount effective to down-regulate PD1 and/or PDL1.
Regarding claim 18, Gunn teaches that biomarkers may be used to identify responders or non-responders to a particular SSI, or as a marker of efficacious dosing in a dose adjustment period (see pg. 38, para. [0354]). Gunn also teaches that PD1 and PDL1 may be used as biomarkers indicative of treatment efficacy (see pg. 41, para. [0378]). Hence, it would have been obvious to have assayed a sample from the patient for any of these biomarkers in order to determine efficacy and/or efficacious dosing.
Regarding claim 19, Gunn teaches a method of monitoring efficacy of a treatment regime in an individual being treated for an immune dysfunction in a specific tissue, the method involving measuring a characteristic of an immune response in a post-treatment immune sample obtained from the specific tissue after the individual has been subject to the treatment regime for a period of time (see pg. 18, para. [0216]). Gunn also teaches the measuring of biomarkers to determine effective dosing, as discussed regarding claims 15 and 18. Matzner teaches that the removal of primary tumors often results in decreased production of tumor-secreted and/or tumor-associated immunosuppressive factors, such as IL-10 and TGFβ, secreted by tumor-associated macrophages, and thus immunotherapy might have increased effectiveness in enhancing immune capacity to eradicate minimal residual disease (MRD) when applied during the immediate perioperative period (IPP) (see pg. 317, col. 2, para. 2 to col. 1, para. 1). Hence, it would have been obvious to have monitored immune suppression in the subject by assaying a patient sample for IL-10 and TGFβ, because Matzner teaches these compounds to be tumor-associated immunosuppressive factors. Accordingly, one would have recognized that these factors could be used to monitor efficacy of the treatment regime.
Regarding claim 20, Gunn teaches the composition is administered at an administration site that is not the target tissue (see claim 19).
Regarding claim 22, Gunn teaches the administration site is the skin or subcutaneous tissue (see claim 20).
Regarding claim 24, Gunn teaches the composition is administered in a plurality
of doses over a dosage duration, and the dosage duration is at least two weeks (see claim 25).
Regarding claim 25, Gunn teaches the doses are administered subcutaneously every day, or every other day (see claim 26). As discussed above, Matzner teaches anti-metastatic interventions, such as immunotherapy, may be more effective when administered within the immediate perioperative period (IPP), spanning a few days before and after surgery (including the surgical period itself). Hence, it would have been obvious to have administered the composition before and after the surgery date.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 2, 6-7, 17-20, 22 and 24-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3, 14, 19, 29 and 32-33 of copending Application No. 16/957,505 in view of Matzner.
This is a provisional nonstatutory double patenting rejection.
Regarding claim 2, claim 3 of ‘505 recites a method of enhancing an anti-tumor efficacy of an adoptive immune cell against cancer (i.e., a method to treat cancer) in a mammalian subject, wherein the cancer forms a tumor in a target tissue, the treatment comprising administering to the subject an effective amount of an immunogenic composition, wherein the immunogenic composition comprises a whole killed bacterial cell of either (a) Escherichia coli, wherein the target tissue is the ovary or colon or (b) Klebsiella pneumonia, wherein the target tissue is the lung.
Claim 3 of ‘505 does not teach that the administration of the immunogenic composition is during a perioperative period that is within one month of the surgery date that the tumor is removed.
However, in view of the teachings of Matzner, discussed under 35 U.S.C. 103, it would have been obvious at the time of filing for a person of ordinary skill in the art to have arrived at the claimed invention by combining the teachings of the copending application with that of Matzner, because both references relate to immunostimulatory therapies to treat cancer. Furthermore, Matzner teaches that such therapies, while typically administered up to a month before surgical removal of a tumor to avoid complications, may actually be more efficacious when administered closer to the surgery date. Hence, one would have immediately recognized the benefits of administering the immunogenic composition recited in the copending claims during a period that is within less than a month, even within a few days, of the surgery date. Further, Matzner teaches such anti-metastatic interventions during the immediate perioperative period in combination with the surgical removal of a primary tumor to have a synergistic effect on treating cancer. Hence, one would have been particularly motivated to apply the combination in order to increase the efficacy of the cancer treatments and to reduce the risk of cancer recurrence. One would have also have had a reasonable expectation of success, because both approaches to treat cancer (i.e., immunogenic therapies, surgery) are commonly known in the art and both are taught by Matzner to work synergistically when used in combination. Hence, the combination would have been readily apparent and deemed to be a mere (A) combining of prior art elements according to known methods to yield predictable results (see MPEP 2143(I): Rationales to support rejections under 35 U.S.C. 103).
Regarding claim 6, the claim is obvious for the same reasons discussed under 35 U.S.C. 103.
Regarding claim 7, claim 14 of ‘505 recites “The method of claim 3, wherein the subject is a mouse, cat, dog, horse, rodent or human.”
Regarding claim 17, claim 19 of ‘505 recites “The method of claim 3, wherein the immunogenic composition upregulates expression of CXCL9 or CXCL10.” Hence, it would have been obvious to have administered the composition in an amount effective to upregulate chemokines CXCL9 & CXCL10.
Regarding claim 18, claim 29 of ‘505 recites “The method of claim 3, further comprising measuring the level of a biomarker in the subject selected from the group consisting of PD1, PDL1, neutrophils, and NKG2D”. Hence, it would have been obvious to have assayed a sample from the patient for the biomarker.
Regarding claim 19, claim 29 of ‘505 recites “The method of claim 3, further comprising measuring the level of a biomarker in the subject selected from the group consisting of PD1, PDL1, neutrophils, and NKG2D”. Hence, it would have been obvious to have monitored an immune response in the subject by assaying a patient sample for NKG2D ligands expressed on human cells. It would have also been obvious to have monitored immune suppression in the subject by assaying a patient sample for IL-10 and TGFβ, because Matzner teaches these compounds to be tumor-associated immunosuppressive factors, as discussed under 35 USC 103. Accordingly, one would have recognized that these factors could be used to monitor efficacy of the treatment regime.
Regarding claim 20, claim 32 of ‘505 recites “The method of claim 3, wherein the immunogenic composition is administered at an administration site that is not the target tissue.”
Regarding claim 22, claim 33 of ‘505 recites “The method of claim 32, wherein the administration site is the skin or subcutaneous tissue.”
Regarding claim 24, claim 3 of ‘505 recites wherein “the immunogenic composition is administered in a plurality of doses over a dosage duration, and the dosage duration is at least two weeks”.
Regarding claim 25, claim 3 of ‘505 recites wherein “the doses are administered subcutaneously every day, or every other day”. As discussed under 35 U.S.C. 103, Matzner teaches anti-metastatic interventions, such as immunotherapy, may be more effective when administered within the immediate perioperative period (IPP), spanning a few days before and after surgery (including the surgical period itself). Hence, it would have been obvious to have administered the composition before and after the surgery date.
Claims 13-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3, 14, 19, 29 and 32-33 of copending Application No. 16/957,505 in view of Matzner, as applied to claims 2, 6-7, 17-20, 22 and 24-25 above, and further in view of Gunn.
This is a provisional nonstatutory double patenting rejection.
Regarding claim 13, as discussed under 35 USC 103, Gunn teaches: the use of an immunogenic composition in methods of treating an immune dysregulation in a target tissue of a mammalian host suffering from a disease or condition characterized by the immune dysregulation of the target tissue, such as a cancer; a preparation of killed or attenuated microbes of one or more pathogenic microbial species, wherein the pathogenic microbial species is pathogenic in the corresponding specific organ or tissue in a healthy subject; that the pathogenic bacterial species are administered to an individual in an amount effective to stop or slow progression or metastasis of the cancer, or to increase survival of the subject; and that the microbial pathogens have a mammalian pattern recognition receptor (PRR) signature that is specific to the target tissue wherein the microbe is pathogenic.
Gunn also teaches the use of the preparation, wherein (a) the subject’s cancer is situated in the target tissue of the ovary or colon and the pathogenic microbial species is Escherichia coli or (b) the subject’s cancer is situated in the target tissue of the lung and the pathogenic microbial species is Klebsiella pneumoniae (see claims 8 and 39).
Hence, both Gunn and the claims of ‘505 teach the same immunogenic composition for use in methods to treat cancer, and it would have been obvious to have combined the teachings of the copending claims with that of Gunn and Matzner for the same reasons discussed under 35 USC 103 and in the NSDP rejections of claims 2, 6-7, 17-20, 22 and 24-25 above.
Gunn further teaches the composition may be adapted for use in an amount effective to modulate a biomarker (see pg. 2, para. [0011]). Example 29 of Gunn’s disclosure illustrates that site specific immunotherapies (administration of whole killed cells of a pathogenic bacteria) potentiate an immune response when used in combination with cancer antigens (see pg. 44, para. [0402]; pg. 27, para. [0269]). The results of this study showed that the site specific immunotherapy treatment, with or without the antigen, enhanced circulating levels of IFN-γ (see pg. 44, para. [0406]). Hence, it would have been obvious to have selected IFN-γ as the biomarker.
Regarding claim 14, Gunn teaches the composition may be adapted for use in an amount effective to modulate a biomarker, for example, neutrophils (see pg. 2, para. [0011]). Gunn teaches that the immunogenic composition may activate or expand neutrophils of the immune system (see pg. 17, para. [0213]) and elevated neutrophils in the blood of treated mice was demonstrated in several Examples of the disclosure (see, e.g., pg. 5, para. [0082] and FIG. 66). Hence, it would have been obvious to have administered the composition in an amount effective to increase neutrophil cell counts.
Regarding claim 15, Gunn teaches the composition may be used in an amount effective to modulate a biomarker selected from the group consisting of PD1, PDL1, IP-10, MIG, RANTES, neutrophils, Ly6C monocytes, and NKG2D (see claim 14). Hence, it would have been obvious to have administered the composition in an amount effective to modulate any of these biomarkers.
Regarding claim 16, Gunn teaches the composition is for use in an amount effective to down-regulate PD1 and/or PDL1 expression in cells present in the target tissue (see claim 15). Hence, it would have been obvious to have administered the composition in an amount effective to down-regulate PD1 and/or PDL1 expression in cells present in the target tissue.
Conclusion
No claims are allowed.
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